annotation_CSV/PMC4802085.csv

anno_start	anno_end	anno_text	entity_type	sentence	section
0	4	Haem	chemical	Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance	TITLE
15	27	dimerization	oligomeric_state	Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance	TITLE
31	37	PGRMC1	protein	Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance	TITLE
38	45	Sigma-2	protein	Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance	TITLE
0	42	Progesterone-receptor membrane component 1	protein	Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown.	ABSTRACT
44	50	PGRMC1	protein	Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown.	ABSTRACT
51	67	Sigma-2 receptor	protein	Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown.	ABSTRACT
74	97	haem-containing protein	protein_type	Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown.	ABSTRACT
118	150	epidermal growth factor receptor	protein_type	Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown.	ABSTRACT
152	156	EGFR	protein_type	Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown.	ABSTRACT
162	178	cytochromes P450	protein_type	Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem-containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown.	ABSTRACT
5	30	crystallographic analyses	experimental_method	Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 Å resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules.	ABSTRACT
38	44	PGRMC1	protein	Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 Å resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules.	ABSTRACT
45	61	cytosolic domain	structure_element	Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 Å resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules.	ABSTRACT
106	112	stable	protein_state	Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 Å resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules.	ABSTRACT
113	118	dimer	oligomeric_state	Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 Å resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules.	ABSTRACT
127	148	stacking interactions	bond_interaction	Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 Å resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules.	ABSTRACT
167	171	haem	chemical	Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 Å resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules.	ABSTRACT
4	8	haem	chemical	The haem iron is five-coordinated by Tyr113, and the open surface of the haem mediates dimerization.	ABSTRACT
9	13	iron	chemical	The haem iron is five-coordinated by Tyr113, and the open surface of the haem mediates dimerization.	ABSTRACT
17	36	five-coordinated by	bond_interaction	The haem iron is five-coordinated by Tyr113, and the open surface of the haem mediates dimerization.	ABSTRACT
37	43	Tyr113	residue_name_number	The haem iron is five-coordinated by Tyr113, and the open surface of the haem mediates dimerization.	ABSTRACT
58	65	surface	site	The haem iron is five-coordinated by Tyr113, and the open surface of the haem mediates dimerization.	ABSTRACT
73	77	haem	chemical	The haem iron is five-coordinated by Tyr113, and the open surface of the haem mediates dimerization.	ABSTRACT
87	99	dimerization	oligomeric_state	The haem iron is five-coordinated by Tyr113, and the open surface of the haem mediates dimerization.	ABSTRACT
0	15	Carbon monoxide	chemical	Carbon monoxide (CO) interferes with PGRMC1 dimerization by binding to the sixth coordination site of the haem.	ABSTRACT
17	19	CO	chemical	Carbon monoxide (CO) interferes with PGRMC1 dimerization by binding to the sixth coordination site of the haem.	ABSTRACT
37	43	PGRMC1	protein	Carbon monoxide (CO) interferes with PGRMC1 dimerization by binding to the sixth coordination site of the haem.	ABSTRACT
44	56	dimerization	oligomeric_state	Carbon monoxide (CO) interferes with PGRMC1 dimerization by binding to the sixth coordination site of the haem.	ABSTRACT
75	98	sixth coordination site	site	Carbon monoxide (CO) interferes with PGRMC1 dimerization by binding to the sixth coordination site of the haem.	ABSTRACT
106	110	haem	chemical	Carbon monoxide (CO) interferes with PGRMC1 dimerization by binding to the sixth coordination site of the haem.	ABSTRACT
0	4	Haem	chemical	Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells.	ABSTRACT
14	20	PGRMC1	protein	Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells.	ABSTRACT
21	33	dimerization	oligomeric_state	Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells.	ABSTRACT
68	72	EGFR	protein_type	Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells.	ABSTRACT
77	93	cytochromes P450	protein_type	Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells.	ABSTRACT
201	203	CO	chemical	Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells.	ABSTRACT
207	211	haem	chemical	Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells.	ABSTRACT
32	44	dimerization	oligomeric_state	This study demonstrates protein dimerization via haem–haem stacking, which has not been seen in eukaryotes, and provides insights into its functional significance in cancer.	ABSTRACT
49	67	haem–haem stacking	bond_interaction	This study demonstrates protein dimerization via haem–haem stacking, which has not been seen in eukaryotes, and provides insights into its functional significance in cancer.	ABSTRACT
96	106	eukaryotes	taxonomy_domain	This study demonstrates protein dimerization via haem–haem stacking, which has not been seen in eukaryotes, and provides insights into its functional significance in cancer.	ABSTRACT
1	7	PGRMC1	protein	 PGRMC1 binds to EGFR and cytochromes P450, and is known to be involved in cancer proliferation and in drug resistance.	ABSTRACT
17	21	EGFR	protein_type	 PGRMC1 binds to EGFR and cytochromes P450, and is known to be involved in cancer proliferation and in drug resistance.	ABSTRACT
26	42	cytochromes P450	protein_type	 PGRMC1 binds to EGFR and cytochromes P450, and is known to be involved in cancer proliferation and in drug resistance.	ABSTRACT
32	41	structure	evidence	Here, the authors determine the structure of the cytosolic domain of PGRMC1, which forms a dimer via haem–haem stacking, and propose how this interaction could be involved in its function.	ABSTRACT
49	65	cytosolic domain	structure_element	Here, the authors determine the structure of the cytosolic domain of PGRMC1, which forms a dimer via haem–haem stacking, and propose how this interaction could be involved in its function.	ABSTRACT
69	75	PGRMC1	protein	Here, the authors determine the structure of the cytosolic domain of PGRMC1, which forms a dimer via haem–haem stacking, and propose how this interaction could be involved in its function.	ABSTRACT
91	96	dimer	oligomeric_state	Here, the authors determine the structure of the cytosolic domain of PGRMC1, which forms a dimer via haem–haem stacking, and propose how this interaction could be involved in its function.	ABSTRACT
101	119	haem–haem stacking	bond_interaction	Here, the authors determine the structure of the cytosolic domain of PGRMC1, which forms a dimer via haem–haem stacking, and propose how this interaction could be involved in its function.	ABSTRACT
45	49	haem	chemical	Much attention has been paid to the roles of haem-iron in cancer development.	INTRO
50	54	iron	chemical	Much attention has been paid to the roles of haem-iron in cancer development.	INTRO
28	32	haem	chemical	Increased dietary intake of haem is a risk factor for several types of cancer.	INTRO
29	43	deprivation of	protein_state	Previous studies showed that deprivation of iron or haem suppresses tumourigenesis.	INTRO
44	48	iron	chemical	Previous studies showed that deprivation of iron or haem suppresses tumourigenesis.	INTRO
52	56	haem	chemical	Previous studies showed that deprivation of iron or haem suppresses tumourigenesis.	INTRO
19	34	carbon monoxide	chemical	On the other hand, carbon monoxide (CO), the gaseous mediator generated by oxidative degradation of haem via haem oxygenase (HO), inhibits tumour growth.	INTRO
36	38	CO	chemical	On the other hand, carbon monoxide (CO), the gaseous mediator generated by oxidative degradation of haem via haem oxygenase (HO), inhibits tumour growth.	INTRO
100	104	haem	chemical	On the other hand, carbon monoxide (CO), the gaseous mediator generated by oxidative degradation of haem via haem oxygenase (HO), inhibits tumour growth.	INTRO
109	123	haem oxygenase	protein_type	On the other hand, carbon monoxide (CO), the gaseous mediator generated by oxidative degradation of haem via haem oxygenase (HO), inhibits tumour growth.	INTRO
125	127	HO	protein_type	On the other hand, carbon monoxide (CO), the gaseous mediator generated by oxidative degradation of haem via haem oxygenase (HO), inhibits tumour growth.	INTRO
37	41	haem	chemical	Thus, a tenuous balance between free haem and CO plays key roles in cancer development and chemoresistance, although the underlying mechanisms are not fully understood.	INTRO
46	48	CO	chemical	Thus, a tenuous balance between free haem and CO plays key roles in cancer development and chemoresistance, although the underlying mechanisms are not fully understood.	INTRO
93	111	affinity nanobeads	experimental_method	To gain insight into the underlying mechanisms, we took chemical biological approaches using affinity nanobeads carrying haem and identified progesterone-receptor membrane component 1 (PGRMC1) as a haem-binding protein from mouse liver extracts (Supplementary Fig. 1).	INTRO
121	125	haem	chemical	To gain insight into the underlying mechanisms, we took chemical biological approaches using affinity nanobeads carrying haem and identified progesterone-receptor membrane component 1 (PGRMC1) as a haem-binding protein from mouse liver extracts (Supplementary Fig. 1).	INTRO
141	183	progesterone-receptor membrane component 1	protein	To gain insight into the underlying mechanisms, we took chemical biological approaches using affinity nanobeads carrying haem and identified progesterone-receptor membrane component 1 (PGRMC1) as a haem-binding protein from mouse liver extracts (Supplementary Fig. 1).	INTRO
185	191	PGRMC1	protein	To gain insight into the underlying mechanisms, we took chemical biological approaches using affinity nanobeads carrying haem and identified progesterone-receptor membrane component 1 (PGRMC1) as a haem-binding protein from mouse liver extracts (Supplementary Fig. 1).	INTRO
198	202	haem	chemical	To gain insight into the underlying mechanisms, we took chemical biological approaches using affinity nanobeads carrying haem and identified progesterone-receptor membrane component 1 (PGRMC1) as a haem-binding protein from mouse liver extracts (Supplementary Fig. 1).	INTRO
224	229	mouse	taxonomy_domain	To gain insight into the underlying mechanisms, we took chemical biological approaches using affinity nanobeads carrying haem and identified progesterone-receptor membrane component 1 (PGRMC1) as a haem-binding protein from mouse liver extracts (Supplementary Fig. 1).	INTRO
0	6	PGRMC1	protein	PGRMC1 is a member of the membrane-associated progesterone receptor (MAPR) family with a cytochrome b5-like haem-binding region, and is known to be highly expressed in various types of cancers.	INTRO
26	67	membrane-associated progesterone receptor	protein_type	PGRMC1 is a member of the membrane-associated progesterone receptor (MAPR) family with a cytochrome b5-like haem-binding region, and is known to be highly expressed in various types of cancers.	INTRO
69	73	MAPR	protein_type	PGRMC1 is a member of the membrane-associated progesterone receptor (MAPR) family with a cytochrome b5-like haem-binding region, and is known to be highly expressed in various types of cancers.	INTRO
89	107	cytochrome b5-like	structure_element	PGRMC1 is a member of the membrane-associated progesterone receptor (MAPR) family with a cytochrome b5-like haem-binding region, and is known to be highly expressed in various types of cancers.	INTRO
108	127	haem-binding region	site	PGRMC1 is a member of the membrane-associated progesterone receptor (MAPR) family with a cytochrome b5-like haem-binding region, and is known to be highly expressed in various types of cancers.	INTRO
148	164	highly expressed	protein_state	PGRMC1 is a member of the membrane-associated progesterone receptor (MAPR) family with a cytochrome b5-like haem-binding region, and is known to be highly expressed in various types of cancers.	INTRO
0	6	PGRMC1	protein	PGRMC1 is anchored to the cell membrane through the N-terminal transmembrane helix and interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 (ref).	INTRO
63	82	transmembrane helix	structure_element	PGRMC1 is anchored to the cell membrane through the N-terminal transmembrane helix and interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 (ref).	INTRO
102	134	epidermal growth factor receptor	protein_type	PGRMC1 is anchored to the cell membrane through the N-terminal transmembrane helix and interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 (ref).	INTRO
136	140	EGFR	protein_type	PGRMC1 is anchored to the cell membrane through the N-terminal transmembrane helix and interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 (ref).	INTRO
146	162	cytochromes P450	protein_type	PGRMC1 is anchored to the cell membrane through the N-terminal transmembrane helix and interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 (ref).	INTRO
6	12	PGRMC1	protein	While PGRMC1 is implicated in cell proliferation and cholesterol biosynthesis, the structural basis on which PGRMC1 exerts its function remains largely unknown.	INTRO
109	115	PGRMC1	protein	While PGRMC1 is implicated in cell proliferation and cholesterol biosynthesis, the structural basis on which PGRMC1 exerts its function remains largely unknown.	INTRO
18	24	PGRMC1	protein	Here we show that PGRMC1 exhibits a unique haem-dependent dimerization.	INTRO
43	47	haem	chemical	Here we show that PGRMC1 exhibits a unique haem-dependent dimerization.	INTRO
58	70	dimerization	oligomeric_state	Here we show that PGRMC1 exhibits a unique haem-dependent dimerization.	INTRO
4	9	dimer	oligomeric_state	The dimer binds to EGFR and cytochromes P450 to enhance tumour cell proliferation and chemoresistance.	INTRO
19	23	EGFR	protein_type	The dimer binds to EGFR and cytochromes P450 to enhance tumour cell proliferation and chemoresistance.	INTRO
28	44	cytochromes P450	protein_type	The dimer binds to EGFR and cytochromes P450 to enhance tumour cell proliferation and chemoresistance.	INTRO
4	9	dimer	oligomeric_state	The dimer is dissociated to monomers by physiological levels of CO, suggesting that PGRMC1 serves as a CO-sensitive molecular switch regulating cancer cell proliferation.	INTRO
28	36	monomers	oligomeric_state	The dimer is dissociated to monomers by physiological levels of CO, suggesting that PGRMC1 serves as a CO-sensitive molecular switch regulating cancer cell proliferation.	INTRO
64	66	CO	chemical	The dimer is dissociated to monomers by physiological levels of CO, suggesting that PGRMC1 serves as a CO-sensitive molecular switch regulating cancer cell proliferation.	INTRO
84	90	PGRMC1	protein	The dimer is dissociated to monomers by physiological levels of CO, suggesting that PGRMC1 serves as a CO-sensitive molecular switch regulating cancer cell proliferation.	INTRO
103	105	CO	chemical	The dimer is dissociated to monomers by physiological levels of CO, suggesting that PGRMC1 serves as a CO-sensitive molecular switch regulating cancer cell proliferation.	INTRO
0	23	X-ray crystal structure	evidence	X-ray crystal structure of PGRMC1	RESULTS
27	33	PGRMC1	protein	X-ray crystal structure of PGRMC1	RESULTS
3	9	solved	experimental_method	We solved the crystal structure of the haem-bound PGRMC1 cytosolic domain (a.a.72–195) at 1.95 Å resolution (Supplementary Fig. 2).	RESULTS
14	31	crystal structure	evidence	We solved the crystal structure of the haem-bound PGRMC1 cytosolic domain (a.a.72–195) at 1.95 Å resolution (Supplementary Fig. 2).	RESULTS
39	49	haem-bound	protein_state	We solved the crystal structure of the haem-bound PGRMC1 cytosolic domain (a.a.72–195) at 1.95 Å resolution (Supplementary Fig. 2).	RESULTS
50	56	PGRMC1	protein	We solved the crystal structure of the haem-bound PGRMC1 cytosolic domain (a.a.72–195) at 1.95 Å resolution (Supplementary Fig. 2).	RESULTS
57	73	cytosolic domain	structure_element	We solved the crystal structure of the haem-bound PGRMC1 cytosolic domain (a.a.72–195) at 1.95 Å resolution (Supplementary Fig. 2).	RESULTS
79	85	72–195	residue_range	We solved the crystal structure of the haem-bound PGRMC1 cytosolic domain (a.a.72–195) at 1.95 Å resolution (Supplementary Fig. 2).	RESULTS
7	18	presence of	protein_state	In the presence of haem, PGRMC1 forms a dimeric structure largely through hydrophobic interactions between the haem moieties of two monomers (Fig. 1a, Table 1 and Supplementary Fig. 3; a stereo-structural image is shown in Supplementary Fig 4).	RESULTS
19	23	haem	chemical	In the presence of haem, PGRMC1 forms a dimeric structure largely through hydrophobic interactions between the haem moieties of two monomers (Fig. 1a, Table 1 and Supplementary Fig. 3; a stereo-structural image is shown in Supplementary Fig 4).	RESULTS
25	31	PGRMC1	protein	In the presence of haem, PGRMC1 forms a dimeric structure largely through hydrophobic interactions between the haem moieties of two monomers (Fig. 1a, Table 1 and Supplementary Fig. 3; a stereo-structural image is shown in Supplementary Fig 4).	RESULTS
40	47	dimeric	oligomeric_state	In the presence of haem, PGRMC1 forms a dimeric structure largely through hydrophobic interactions between the haem moieties of two monomers (Fig. 1a, Table 1 and Supplementary Fig. 3; a stereo-structural image is shown in Supplementary Fig 4).	RESULTS
74	98	hydrophobic interactions	bond_interaction	In the presence of haem, PGRMC1 forms a dimeric structure largely through hydrophobic interactions between the haem moieties of two monomers (Fig. 1a, Table 1 and Supplementary Fig. 3; a stereo-structural image is shown in Supplementary Fig 4).	RESULTS
111	115	haem	chemical	In the presence of haem, PGRMC1 forms a dimeric structure largely through hydrophobic interactions between the haem moieties of two monomers (Fig. 1a, Table 1 and Supplementary Fig. 3; a stereo-structural image is shown in Supplementary Fig 4).	RESULTS
132	140	monomers	oligomeric_state	In the presence of haem, PGRMC1 forms a dimeric structure largely through hydrophobic interactions between the haem moieties of two monomers (Fig. 1a, Table 1 and Supplementary Fig. 3; a stereo-structural image is shown in Supplementary Fig 4).	RESULTS
26	32	PGRMC1	protein	While the overall fold of PGRMC1 is similar to that of canonical cytochrome b5, their haem irons are coordinated differently.	RESULTS
65	78	cytochrome b5	protein_type	While the overall fold of PGRMC1 is similar to that of canonical cytochrome b5, their haem irons are coordinated differently.	RESULTS
86	90	haem	chemical	While the overall fold of PGRMC1 is similar to that of canonical cytochrome b5, their haem irons are coordinated differently.	RESULTS
3	16	cytochrome b5	protein_type	In cytochrome b5, the haem iron is six-coordinated by two axial histidine residues.	RESULTS
22	26	haem	chemical	In cytochrome b5, the haem iron is six-coordinated by two axial histidine residues.	RESULTS
27	31	iron	chemical	In cytochrome b5, the haem iron is six-coordinated by two axial histidine residues.	RESULTS
35	53	six-coordinated by	bond_interaction	In cytochrome b5, the haem iron is six-coordinated by two axial histidine residues.	RESULTS
64	73	histidine	residue_name	In cytochrome b5, the haem iron is six-coordinated by two axial histidine residues.	RESULTS
6	16	histidines	residue_name	These histidines are missing in PGRMC1, and the haem iron is five-coordinated by Tyr113 (Y113) alone (Fig. 1b and Supplementary Fig. 3).	RESULTS
21	28	missing	protein_state	These histidines are missing in PGRMC1, and the haem iron is five-coordinated by Tyr113 (Y113) alone (Fig. 1b and Supplementary Fig. 3).	RESULTS
32	38	PGRMC1	protein	These histidines are missing in PGRMC1, and the haem iron is five-coordinated by Tyr113 (Y113) alone (Fig. 1b and Supplementary Fig. 3).	RESULTS
48	52	haem	chemical	These histidines are missing in PGRMC1, and the haem iron is five-coordinated by Tyr113 (Y113) alone (Fig. 1b and Supplementary Fig. 3).	RESULTS
53	57	iron	chemical	These histidines are missing in PGRMC1, and the haem iron is five-coordinated by Tyr113 (Y113) alone (Fig. 1b and Supplementary Fig. 3).	RESULTS
61	80	five-coordinated by	bond_interaction	These histidines are missing in PGRMC1, and the haem iron is five-coordinated by Tyr113 (Y113) alone (Fig. 1b and Supplementary Fig. 3).	RESULTS
81	87	Tyr113	residue_name_number	These histidines are missing in PGRMC1, and the haem iron is five-coordinated by Tyr113 (Y113) alone (Fig. 1b and Supplementary Fig. 3).	RESULTS
89	93	Y113	residue_name_number	These histidines are missing in PGRMC1, and the haem iron is five-coordinated by Tyr113 (Y113) alone (Fig. 1b and Supplementary Fig. 3).	RESULTS
95	100	alone	protein_state	These histidines are missing in PGRMC1, and the haem iron is five-coordinated by Tyr113 (Y113) alone (Fig. 1b and Supplementary Fig. 3).	RESULTS
2	18	homologous helix	structure_element	A homologous helix that holds haem in cytochrome b5 is longer, shifts away from haem, and does not form a coordinate bond in PGRMC1 (Fig. 1c).	RESULTS
30	34	haem	chemical	A homologous helix that holds haem in cytochrome b5 is longer, shifts away from haem, and does not form a coordinate bond in PGRMC1 (Fig. 1c).	RESULTS
38	51	cytochrome b5	protein_type	A homologous helix that holds haem in cytochrome b5 is longer, shifts away from haem, and does not form a coordinate bond in PGRMC1 (Fig. 1c).	RESULTS
80	84	haem	chemical	A homologous helix that holds haem in cytochrome b5 is longer, shifts away from haem, and does not form a coordinate bond in PGRMC1 (Fig. 1c).	RESULTS
125	131	PGRMC1	protein	A homologous helix that holds haem in cytochrome b5 is longer, shifts away from haem, and does not form a coordinate bond in PGRMC1 (Fig. 1c).	RESULTS
35	39	haem	chemical	Consequently, the five-coordinated haem of PGRMC1 has an open surface that allows its dimerization through hydrophobic haem–haem stacking.	RESULTS
43	49	PGRMC1	protein	Consequently, the five-coordinated haem of PGRMC1 has an open surface that allows its dimerization through hydrophobic haem–haem stacking.	RESULTS
62	69	surface	site	Consequently, the five-coordinated haem of PGRMC1 has an open surface that allows its dimerization through hydrophobic haem–haem stacking.	RESULTS
86	98	dimerization	oligomeric_state	Consequently, the five-coordinated haem of PGRMC1 has an open surface that allows its dimerization through hydrophobic haem–haem stacking.	RESULTS
107	137	hydrophobic haem–haem stacking	bond_interaction	Consequently, the five-coordinated haem of PGRMC1 has an open surface that allows its dimerization through hydrophobic haem–haem stacking.	RESULTS
62	68	Tyr164	residue_name_number	Contrary to our finding, Kaluka et al. recently reported that Tyr164 of PGRMC1 is the axial ligand of haem because mutation of this residue impairs haem binding.	RESULTS
72	78	PGRMC1	protein	Contrary to our finding, Kaluka et al. recently reported that Tyr164 of PGRMC1 is the axial ligand of haem because mutation of this residue impairs haem binding.	RESULTS
102	106	haem	chemical	Contrary to our finding, Kaluka et al. recently reported that Tyr164 of PGRMC1 is the axial ligand of haem because mutation of this residue impairs haem binding.	RESULTS
115	123	mutation	experimental_method	Contrary to our finding, Kaluka et al. recently reported that Tyr164 of PGRMC1 is the axial ligand of haem because mutation of this residue impairs haem binding.	RESULTS
148	152	haem	chemical	Contrary to our finding, Kaluka et al. recently reported that Tyr164 of PGRMC1 is the axial ligand of haem because mutation of this residue impairs haem binding.	RESULTS
4	19	structural data	evidence	Our structural data revealed that Tyr164 and a few other residues such as Tyr107 and Lys163 are in fact hydrogen-bonded to haem propionates.	RESULTS
34	40	Tyr164	residue_name_number	Our structural data revealed that Tyr164 and a few other residues such as Tyr107 and Lys163 are in fact hydrogen-bonded to haem propionates.	RESULTS
74	80	Tyr107	residue_name_number	Our structural data revealed that Tyr164 and a few other residues such as Tyr107 and Lys163 are in fact hydrogen-bonded to haem propionates.	RESULTS
85	91	Lys163	residue_name_number	Our structural data revealed that Tyr164 and a few other residues such as Tyr107 and Lys163 are in fact hydrogen-bonded to haem propionates.	RESULTS
104	119	hydrogen-bonded	bond_interaction	Our structural data revealed that Tyr164 and a few other residues such as Tyr107 and Lys163 are in fact hydrogen-bonded to haem propionates.	RESULTS
123	127	haem	chemical	Our structural data revealed that Tyr164 and a few other residues such as Tyr107 and Lys163 are in fact hydrogen-bonded to haem propionates.	RESULTS
56	63	Tyr 107	residue_name_number	This is consistent with observations by Min et al. that Tyr 107 and Tyr113 of PGRMC1 are involved in binding with haem.	RESULTS
68	74	Tyr113	residue_name_number	This is consistent with observations by Min et al. that Tyr 107 and Tyr113 of PGRMC1 are involved in binding with haem.	RESULTS
78	84	PGRMC1	protein	This is consistent with observations by Min et al. that Tyr 107 and Tyr113 of PGRMC1 are involved in binding with haem.	RESULTS
114	118	haem	chemical	This is consistent with observations by Min et al. that Tyr 107 and Tyr113 of PGRMC1 are involved in binding with haem.	RESULTS
30	39	conserved	protein_state	These amino acid residues are conserved among MAPR family members (Supplementary Fig. 5a), suggesting that these proteins share the ability to exhibit haem-dependent dimerization.	RESULTS
46	50	MAPR	protein_type	These amino acid residues are conserved among MAPR family members (Supplementary Fig. 5a), suggesting that these proteins share the ability to exhibit haem-dependent dimerization.	RESULTS
151	155	haem	chemical	These amino acid residues are conserved among MAPR family members (Supplementary Fig. 5a), suggesting that these proteins share the ability to exhibit haem-dependent dimerization.	RESULTS
166	178	dimerization	oligomeric_state	These amino acid residues are conserved among MAPR family members (Supplementary Fig. 5a), suggesting that these proteins share the ability to exhibit haem-dependent dimerization.	RESULTS
0	6	PGRMC1	protein	PGRMC1 exhibits haem-dependent dimerization in solution	RESULTS
16	20	haem	chemical	PGRMC1 exhibits haem-dependent dimerization in solution	RESULTS
31	43	dimerization	oligomeric_state	PGRMC1 exhibits haem-dependent dimerization in solution	RESULTS
7	13	PGRMC1	protein	In the PGRMC1 crystal, two different types of crystal contacts (chain A–A″ and A–B) were observed in addition to the haem-mediated dimer (chain A–A′) (Supplementary Figs 3 and 6a).	RESULTS
14	21	crystal	evidence	In the PGRMC1 crystal, two different types of crystal contacts (chain A–A″ and A–B) were observed in addition to the haem-mediated dimer (chain A–A′) (Supplementary Figs 3 and 6a).	RESULTS
117	121	haem	chemical	In the PGRMC1 crystal, two different types of crystal contacts (chain A–A″ and A–B) were observed in addition to the haem-mediated dimer (chain A–A′) (Supplementary Figs 3 and 6a).	RESULTS
131	136	dimer	oligomeric_state	In the PGRMC1 crystal, two different types of crystal contacts (chain A–A″ and A–B) were observed in addition to the haem-mediated dimer (chain A–A′) (Supplementary Figs 3 and 6a).	RESULTS
16	20	haem	chemical	To confirm that haem-assisted dimerization of PGRMC1 occurs in solution, we analysed the structure of apo- and haem-bound PGMRC1 by two-dimensional nuclear magnetic resonance (NMR) using heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy (Supplementary Figs 6b and 7).	RESULTS
30	42	dimerization	oligomeric_state	To confirm that haem-assisted dimerization of PGRMC1 occurs in solution, we analysed the structure of apo- and haem-bound PGMRC1 by two-dimensional nuclear magnetic resonance (NMR) using heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy (Supplementary Figs 6b and 7).	RESULTS
46	52	PGRMC1	protein	To confirm that haem-assisted dimerization of PGRMC1 occurs in solution, we analysed the structure of apo- and haem-bound PGMRC1 by two-dimensional nuclear magnetic resonance (NMR) using heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy (Supplementary Figs 6b and 7).	RESULTS
89	98	structure	evidence	To confirm that haem-assisted dimerization of PGRMC1 occurs in solution, we analysed the structure of apo- and haem-bound PGMRC1 by two-dimensional nuclear magnetic resonance (NMR) using heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy (Supplementary Figs 6b and 7).	RESULTS
102	105	apo	protein_state	To confirm that haem-assisted dimerization of PGRMC1 occurs in solution, we analysed the structure of apo- and haem-bound PGMRC1 by two-dimensional nuclear magnetic resonance (NMR) using heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy (Supplementary Figs 6b and 7).	RESULTS
111	121	haem-bound	protein_state	To confirm that haem-assisted dimerization of PGRMC1 occurs in solution, we analysed the structure of apo- and haem-bound PGMRC1 by two-dimensional nuclear magnetic resonance (NMR) using heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy (Supplementary Figs 6b and 7).	RESULTS
122	128	PGMRC1	protein	To confirm that haem-assisted dimerization of PGRMC1 occurs in solution, we analysed the structure of apo- and haem-bound PGMRC1 by two-dimensional nuclear magnetic resonance (NMR) using heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy (Supplementary Figs 6b and 7).	RESULTS
132	174	two-dimensional nuclear magnetic resonance	experimental_method	To confirm that haem-assisted dimerization of PGRMC1 occurs in solution, we analysed the structure of apo- and haem-bound PGMRC1 by two-dimensional nuclear magnetic resonance (NMR) using heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy (Supplementary Figs 6b and 7).	RESULTS
176	179	NMR	experimental_method	To confirm that haem-assisted dimerization of PGRMC1 occurs in solution, we analysed the structure of apo- and haem-bound PGMRC1 by two-dimensional nuclear magnetic resonance (NMR) using heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy (Supplementary Figs 6b and 7).	RESULTS
187	274	heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy	experimental_method	To confirm that haem-assisted dimerization of PGRMC1 occurs in solution, we analysed the structure of apo- and haem-bound PGMRC1 by two-dimensional nuclear magnetic resonance (NMR) using heteronuclear single-quantum coherence and transverse relaxation-optimized spectroscopy (Supplementary Figs 6b and 7).	RESULTS
0	3	NMR	experimental_method	NMR signals from some amino acid residues of PGRMC1 disappeared due to the paramagnetic relaxation effect of haem (Supplementary Figs 6b); these residues were located in the haem-binding region.	RESULTS
45	51	PGRMC1	protein	NMR signals from some amino acid residues of PGRMC1 disappeared due to the paramagnetic relaxation effect of haem (Supplementary Figs 6b); these residues were located in the haem-binding region.	RESULTS
109	113	haem	chemical	NMR signals from some amino acid residues of PGRMC1 disappeared due to the paramagnetic relaxation effect of haem (Supplementary Figs 6b); these residues were located in the haem-binding region.	RESULTS
174	193	haem-binding region	site	NMR signals from some amino acid residues of PGRMC1 disappeared due to the paramagnetic relaxation effect of haem (Supplementary Figs 6b); these residues were located in the haem-binding region.	RESULTS
5	20	chemical shifts	evidence	When chemical shifts of apo- and haem-bound forms of PGMRC1 were compared, some amino acid residues close to those which disappeared because of the paramagnetic relaxation effect of haem exhibit notable chemical shifts (Supplementary Fig. 6a,b; dark yellow).	RESULTS
24	27	apo	protein_state	When chemical shifts of apo- and haem-bound forms of PGMRC1 were compared, some amino acid residues close to those which disappeared because of the paramagnetic relaxation effect of haem exhibit notable chemical shifts (Supplementary Fig. 6a,b; dark yellow).	RESULTS
33	43	haem-bound	protein_state	When chemical shifts of apo- and haem-bound forms of PGMRC1 were compared, some amino acid residues close to those which disappeared because of the paramagnetic relaxation effect of haem exhibit notable chemical shifts (Supplementary Fig. 6a,b; dark yellow).	RESULTS
53	59	PGMRC1	protein	When chemical shifts of apo- and haem-bound forms of PGMRC1 were compared, some amino acid residues close to those which disappeared because of the paramagnetic relaxation effect of haem exhibit notable chemical shifts (Supplementary Fig. 6a,b; dark yellow).	RESULTS
182	186	haem	chemical	When chemical shifts of apo- and haem-bound forms of PGMRC1 were compared, some amino acid residues close to those which disappeared because of the paramagnetic relaxation effect of haem exhibit notable chemical shifts (Supplementary Fig. 6a,b; dark yellow).	RESULTS
16	26	interfaces	site	However, at the interfaces of the other possible dimeric structures (Supplementary Fig. 6a, chain A–A″; cyan and chain A–B; violet), no significant difference was observed.	RESULTS
49	56	dimeric	oligomeric_state	However, at the interfaces of the other possible dimeric structures (Supplementary Fig. 6a, chain A–A″; cyan and chain A–B; violet), no significant difference was observed.	RESULTS
57	67	structures	evidence	However, at the interfaces of the other possible dimeric structures (Supplementary Fig. 6a, chain A–A″; cyan and chain A–B; violet), no significant difference was observed.	RESULTS
13	40	free energy of dissociation	evidence	Furthermore, free energy of dissociation predicted by PISA suggested that the haem-mediated dimer is stable in solution while the other potential interactions are not.	RESULTS
54	58	PISA	experimental_method	Furthermore, free energy of dissociation predicted by PISA suggested that the haem-mediated dimer is stable in solution while the other potential interactions are not.	RESULTS
78	82	haem	chemical	Furthermore, free energy of dissociation predicted by PISA suggested that the haem-mediated dimer is stable in solution while the other potential interactions are not.	RESULTS
92	97	dimer	oligomeric_state	Furthermore, free energy of dissociation predicted by PISA suggested that the haem-mediated dimer is stable in solution while the other potential interactions are not.	RESULTS
101	107	stable	protein_state	Furthermore, free energy of dissociation predicted by PISA suggested that the haem-mediated dimer is stable in solution while the other potential interactions are not.	RESULTS
56	62	PGRMC1	protein	We also attempted to predict the secondary structure of PGRMC1 through NMR data by calculating with TALOS+ program (Supplementary Fig. 8); the prediction suggested that the overall secondary structure is comparable between apo- and haem-bound forms of PGRMC1 in solution.	RESULTS
71	74	NMR	experimental_method	We also attempted to predict the secondary structure of PGRMC1 through NMR data by calculating with TALOS+ program (Supplementary Fig. 8); the prediction suggested that the overall secondary structure is comparable between apo- and haem-bound forms of PGRMC1 in solution.	RESULTS
100	114	TALOS+ program	experimental_method	We also attempted to predict the secondary structure of PGRMC1 through NMR data by calculating with TALOS+ program (Supplementary Fig. 8); the prediction suggested that the overall secondary structure is comparable between apo- and haem-bound forms of PGRMC1 in solution.	RESULTS
223	226	apo	protein_state	We also attempted to predict the secondary structure of PGRMC1 through NMR data by calculating with TALOS+ program (Supplementary Fig. 8); the prediction suggested that the overall secondary structure is comparable between apo- and haem-bound forms of PGRMC1 in solution.	RESULTS
232	242	haem-bound	protein_state	We also attempted to predict the secondary structure of PGRMC1 through NMR data by calculating with TALOS+ program (Supplementary Fig. 8); the prediction suggested that the overall secondary structure is comparable between apo- and haem-bound forms of PGRMC1 in solution.	RESULTS
252	258	PGRMC1	protein	We also attempted to predict the secondary structure of PGRMC1 through NMR data by calculating with TALOS+ program (Supplementary Fig. 8); the prediction suggested that the overall secondary structure is comparable between apo- and haem-bound forms of PGRMC1 in solution.	RESULTS
16	20	haem	chemical	We analysed the haem-dependent dimerization of the PGRMC1 cytosolic domain (a.a.44–195) in solution (Fig. 2 and Table 2).	RESULTS
31	43	dimerization	oligomeric_state	We analysed the haem-dependent dimerization of the PGRMC1 cytosolic domain (a.a.44–195) in solution (Fig. 2 and Table 2).	RESULTS
51	57	PGRMC1	protein	We analysed the haem-dependent dimerization of the PGRMC1 cytosolic domain (a.a.44–195) in solution (Fig. 2 and Table 2).	RESULTS
58	74	cytosolic domain	structure_element	We analysed the haem-dependent dimerization of the PGRMC1 cytosolic domain (a.a.44–195) in solution (Fig. 2 and Table 2).	RESULTS
80	86	44–195	residue_range	We analysed the haem-dependent dimerization of the PGRMC1 cytosolic domain (a.a.44–195) in solution (Fig. 2 and Table 2).	RESULTS
0	17	Mass spectrometry	experimental_method	Mass spectrometry (MS) analyses under non-denaturing condition demonstrated that the apo-monomer PGRMC1 resulted in dimerization by binding with haem (Fig. 2a).	RESULTS
19	21	MS	experimental_method	Mass spectrometry (MS) analyses under non-denaturing condition demonstrated that the apo-monomer PGRMC1 resulted in dimerization by binding with haem (Fig. 2a).	RESULTS
38	62	non-denaturing condition	experimental_method	Mass spectrometry (MS) analyses under non-denaturing condition demonstrated that the apo-monomer PGRMC1 resulted in dimerization by binding with haem (Fig. 2a).	RESULTS
85	88	apo	protein_state	Mass spectrometry (MS) analyses under non-denaturing condition demonstrated that the apo-monomer PGRMC1 resulted in dimerization by binding with haem (Fig. 2a).	RESULTS
89	96	monomer	oligomeric_state	Mass spectrometry (MS) analyses under non-denaturing condition demonstrated that the apo-monomer PGRMC1 resulted in dimerization by binding with haem (Fig. 2a).	RESULTS
97	103	PGRMC1	protein	Mass spectrometry (MS) analyses under non-denaturing condition demonstrated that the apo-monomer PGRMC1 resulted in dimerization by binding with haem (Fig. 2a).	RESULTS
116	128	dimerization	oligomeric_state	Mass spectrometry (MS) analyses under non-denaturing condition demonstrated that the apo-monomer PGRMC1 resulted in dimerization by binding with haem (Fig. 2a).	RESULTS
145	149	haem	chemical	Mass spectrometry (MS) analyses under non-denaturing condition demonstrated that the apo-monomer PGRMC1 resulted in dimerization by binding with haem (Fig. 2a).	RESULTS
26	40	disulfide bond	ptm	It should be noted that a disulfide bond between two Cys129 residues is observed in the crystal of PGRMC1 (Fig. 1a), while Cys129 is not conserved among the MAPR family proteins (Supplementary Fig. 5a).	RESULTS
53	59	Cys129	residue_name_number	It should be noted that a disulfide bond between two Cys129 residues is observed in the crystal of PGRMC1 (Fig. 1a), while Cys129 is not conserved among the MAPR family proteins (Supplementary Fig. 5a).	RESULTS
88	95	crystal	evidence	It should be noted that a disulfide bond between two Cys129 residues is observed in the crystal of PGRMC1 (Fig. 1a), while Cys129 is not conserved among the MAPR family proteins (Supplementary Fig. 5a).	RESULTS
99	105	PGRMC1	protein	It should be noted that a disulfide bond between two Cys129 residues is observed in the crystal of PGRMC1 (Fig. 1a), while Cys129 is not conserved among the MAPR family proteins (Supplementary Fig. 5a).	RESULTS
123	129	Cys129	residue_name_number	It should be noted that a disulfide bond between two Cys129 residues is observed in the crystal of PGRMC1 (Fig. 1a), while Cys129 is not conserved among the MAPR family proteins (Supplementary Fig. 5a).	RESULTS
133	146	not conserved	protein_state	It should be noted that a disulfide bond between two Cys129 residues is observed in the crystal of PGRMC1 (Fig. 1a), while Cys129 is not conserved among the MAPR family proteins (Supplementary Fig. 5a).	RESULTS
157	161	MAPR	protein_type	It should be noted that a disulfide bond between two Cys129 residues is observed in the crystal of PGRMC1 (Fig. 1a), while Cys129 is not conserved among the MAPR family proteins (Supplementary Fig. 5a).	RESULTS
54	68	disulfide bond	ptm	This observation led us to examine whether or not the disulfide bond contributes to PGRMC1 dimerization.	RESULTS
84	90	PGRMC1	protein	This observation led us to examine whether or not the disulfide bond contributes to PGRMC1 dimerization.	RESULTS
91	103	dimerization	oligomeric_state	This observation led us to examine whether or not the disulfide bond contributes to PGRMC1 dimerization.	RESULTS
0	2	MS	experimental_method	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
18	43	non-denaturing conditions	experimental_method	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
68	77	Cys129Ser	mutant	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
79	84	C129S	mutant	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
86	92	mutant	protein_state	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
96	105	dimerized	protein_state	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
113	124	presence of	protein_state	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
125	129	haem	chemical	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
151	155	haem	chemical	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
165	177	dimerization	oligomeric_state	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
181	187	PGRMC1	protein	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
216	230	disulfide bond	ptm	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
245	251	Cys129	residue_name_number	MS analyses under non-denaturing conditions clearly showed that the Cys129Ser (C129S) mutant is dimerized in the presence of haem, indicating that the haem-mediated dimerization of PGRMC1 occurs independently of the disulfide bond formation via Cys129 (Fig. 2a).	RESULTS
17	19	MS	experimental_method	Supporting this, MS analyses under denaturing conditions showed that haem-mediated PGRMC1 dimer is completely dissociated into monomer, indicating that dimerization of this kind is not mediated by any covalent bond such as disulfide bond (Supplementary Fig. 9).	RESULTS
35	56	denaturing conditions	experimental_method	Supporting this, MS analyses under denaturing conditions showed that haem-mediated PGRMC1 dimer is completely dissociated into monomer, indicating that dimerization of this kind is not mediated by any covalent bond such as disulfide bond (Supplementary Fig. 9).	RESULTS
69	73	haem	chemical	Supporting this, MS analyses under denaturing conditions showed that haem-mediated PGRMC1 dimer is completely dissociated into monomer, indicating that dimerization of this kind is not mediated by any covalent bond such as disulfide bond (Supplementary Fig. 9).	RESULTS
83	89	PGRMC1	protein	Supporting this, MS analyses under denaturing conditions showed that haem-mediated PGRMC1 dimer is completely dissociated into monomer, indicating that dimerization of this kind is not mediated by any covalent bond such as disulfide bond (Supplementary Fig. 9).	RESULTS
90	95	dimer	oligomeric_state	Supporting this, MS analyses under denaturing conditions showed that haem-mediated PGRMC1 dimer is completely dissociated into monomer, indicating that dimerization of this kind is not mediated by any covalent bond such as disulfide bond (Supplementary Fig. 9).	RESULTS
127	134	monomer	oligomeric_state	Supporting this, MS analyses under denaturing conditions showed that haem-mediated PGRMC1 dimer is completely dissociated into monomer, indicating that dimerization of this kind is not mediated by any covalent bond such as disulfide bond (Supplementary Fig. 9).	RESULTS
152	164	dimerization	oligomeric_state	Supporting this, MS analyses under denaturing conditions showed that haem-mediated PGRMC1 dimer is completely dissociated into monomer, indicating that dimerization of this kind is not mediated by any covalent bond such as disulfide bond (Supplementary Fig. 9).	RESULTS
223	237	disulfide bond	ptm	Supporting this, MS analyses under denaturing conditions showed that haem-mediated PGRMC1 dimer is completely dissociated into monomer, indicating that dimerization of this kind is not mediated by any covalent bond such as disulfide bond (Supplementary Fig. 9).	RESULTS
21	25	haem	chemical	We also analysed the haem-dependent dimerization of PGRMC1 by diffusion-ordered NMR spectroscopy (DOSY) analyses (Table 2, Supplementary Fig. 10).	RESULTS
36	48	dimerization	oligomeric_state	We also analysed the haem-dependent dimerization of PGRMC1 by diffusion-ordered NMR spectroscopy (DOSY) analyses (Table 2, Supplementary Fig. 10).	RESULTS
52	58	PGRMC1	protein	We also analysed the haem-dependent dimerization of PGRMC1 by diffusion-ordered NMR spectroscopy (DOSY) analyses (Table 2, Supplementary Fig. 10).	RESULTS
62	96	diffusion-ordered NMR spectroscopy	experimental_method	We also analysed the haem-dependent dimerization of PGRMC1 by diffusion-ordered NMR spectroscopy (DOSY) analyses (Table 2, Supplementary Fig. 10).	RESULTS
98	102	DOSY	experimental_method	We also analysed the haem-dependent dimerization of PGRMC1 by diffusion-ordered NMR spectroscopy (DOSY) analyses (Table 2, Supplementary Fig. 10).	RESULTS
31	50	hydrodynamic radius	evidence	The results suggested that the hydrodynamic radius of haem-bound PGRMC1 is larger than that of apo-PGRMC1.	RESULTS
54	64	haem-bound	protein_state	The results suggested that the hydrodynamic radius of haem-bound PGRMC1 is larger than that of apo-PGRMC1.	RESULTS
65	71	PGRMC1	protein	The results suggested that the hydrodynamic radius of haem-bound PGRMC1 is larger than that of apo-PGRMC1.	RESULTS
95	98	apo	protein_state	The results suggested that the hydrodynamic radius of haem-bound PGRMC1 is larger than that of apo-PGRMC1.	RESULTS
99	105	PGRMC1	protein	The results suggested that the hydrodynamic radius of haem-bound PGRMC1 is larger than that of apo-PGRMC1.	RESULTS
52	64	dimerization	oligomeric_state	To further evaluate changes in molecular weights in dimerization of PGRMC1, sedimentation velocity analytical ultracentrifugation (SV-AUC) analysis was carried out.	RESULTS
68	74	PGRMC1	protein	To further evaluate changes in molecular weights in dimerization of PGRMC1, sedimentation velocity analytical ultracentrifugation (SV-AUC) analysis was carried out.	RESULTS
76	129	sedimentation velocity analytical ultracentrifugation	experimental_method	To further evaluate changes in molecular weights in dimerization of PGRMC1, sedimentation velocity analytical ultracentrifugation (SV-AUC) analysis was carried out.	RESULTS
131	137	SV-AUC	experimental_method	To further evaluate changes in molecular weights in dimerization of PGRMC1, sedimentation velocity analytical ultracentrifugation (SV-AUC) analysis was carried out.	RESULTS
12	21	wild-type	protein_state	Whereas the wild-type (wt) apo-PGRMC1 appeared at a 1.9 S peak as monomer, the haem-binding PGRMC1 was converted into dimer at a 3.1 S peak (Fig. 2b).	RESULTS
23	25	wt	protein_state	Whereas the wild-type (wt) apo-PGRMC1 appeared at a 1.9 S peak as monomer, the haem-binding PGRMC1 was converted into dimer at a 3.1 S peak (Fig. 2b).	RESULTS
27	30	apo	protein_state	Whereas the wild-type (wt) apo-PGRMC1 appeared at a 1.9 S peak as monomer, the haem-binding PGRMC1 was converted into dimer at a 3.1 S peak (Fig. 2b).	RESULTS
31	37	PGRMC1	protein	Whereas the wild-type (wt) apo-PGRMC1 appeared at a 1.9 S peak as monomer, the haem-binding PGRMC1 was converted into dimer at a 3.1 S peak (Fig. 2b).	RESULTS
66	73	monomer	oligomeric_state	Whereas the wild-type (wt) apo-PGRMC1 appeared at a 1.9 S peak as monomer, the haem-binding PGRMC1 was converted into dimer at a 3.1 S peak (Fig. 2b).	RESULTS
79	83	haem	chemical	Whereas the wild-type (wt) apo-PGRMC1 appeared at a 1.9 S peak as monomer, the haem-binding PGRMC1 was converted into dimer at a 3.1 S peak (Fig. 2b).	RESULTS
92	98	PGRMC1	protein	Whereas the wild-type (wt) apo-PGRMC1 appeared at a 1.9 S peak as monomer, the haem-binding PGRMC1 was converted into dimer at a 3.1 S peak (Fig. 2b).	RESULTS
118	123	dimer	oligomeric_state	Whereas the wild-type (wt) apo-PGRMC1 appeared at a 1.9 S peak as monomer, the haem-binding PGRMC1 was converted into dimer at a 3.1 S peak (Fig. 2b).	RESULTS
15	20	C129S	mutant	Similarly, the C129S mutant of PGRMC1 converted from monomer to dimer by binding to haem (Fig. 2b).	RESULTS
21	27	mutant	protein_state	Similarly, the C129S mutant of PGRMC1 converted from monomer to dimer by binding to haem (Fig. 2b).	RESULTS
31	37	PGRMC1	protein	Similarly, the C129S mutant of PGRMC1 converted from monomer to dimer by binding to haem (Fig. 2b).	RESULTS
53	60	monomer	oligomeric_state	Similarly, the C129S mutant of PGRMC1 converted from monomer to dimer by binding to haem (Fig. 2b).	RESULTS
64	69	dimer	oligomeric_state	Similarly, the C129S mutant of PGRMC1 converted from monomer to dimer by binding to haem (Fig. 2b).	RESULTS
84	88	haem	chemical	Similarly, the C129S mutant of PGRMC1 converted from monomer to dimer by binding to haem (Fig. 2b).	RESULTS
0	6	SV-AUC	experimental_method	SV-AUC analyses also allowed us to examine the stability of haem/PGRMC1 dimer.	RESULTS
60	64	haem	chemical	SV-AUC analyses also allowed us to examine the stability of haem/PGRMC1 dimer.	RESULTS
65	71	PGRMC1	protein	SV-AUC analyses also allowed us to examine the stability of haem/PGRMC1 dimer.	RESULTS
72	77	dimer	oligomeric_state	SV-AUC analyses also allowed us to examine the stability of haem/PGRMC1 dimer.	RESULTS
68	78	haem-bound	protein_state	To this end, we used different concentrations (3.5–147 μmol l−1) of haem-bound PGRMC1 protein (a.a. 72–195), which were identical to that used in the crystallographic analysis.	RESULTS
79	85	PGRMC1	protein	To this end, we used different concentrations (3.5–147 μmol l−1) of haem-bound PGRMC1 protein (a.a. 72–195), which were identical to that used in the crystallographic analysis.	RESULTS
100	106	72–195	residue_range	To this end, we used different concentrations (3.5–147 μmol l−1) of haem-bound PGRMC1 protein (a.a. 72–195), which were identical to that used in the crystallographic analysis.	RESULTS
150	175	crystallographic analysis	experimental_method	To this end, we used different concentrations (3.5–147 μmol l−1) of haem-bound PGRMC1 protein (a.a. 72–195), which were identical to that used in the crystallographic analysis.	RESULTS
4	30	sedimentation coefficients	evidence	The sedimentation coefficients calculated on the basis of the crystal structure were 1.71 S for monomer and 2.56 S for dimer (Supplementary Fig. 11, upper panel).	RESULTS
62	79	crystal structure	evidence	The sedimentation coefficients calculated on the basis of the crystal structure were 1.71 S for monomer and 2.56 S for dimer (Supplementary Fig. 11, upper panel).	RESULTS
96	103	monomer	oligomeric_state	The sedimentation coefficients calculated on the basis of the crystal structure were 1.71 S for monomer and 2.56 S for dimer (Supplementary Fig. 11, upper panel).	RESULTS
119	124	dimer	oligomeric_state	The sedimentation coefficients calculated on the basis of the crystal structure were 1.71 S for monomer and 2.56 S for dimer (Supplementary Fig. 11, upper panel).	RESULTS
28	34	PGRMC1	protein	The results showed that the PGRMC1 dimer is not dissociated into monomer at all concentrations examined (Supplementary Fig. 11, lower panel), suggesting that the Kd value of haem-mediated dimer of PGRMC1 is under 3.5 μmol l−1.	RESULTS
35	40	dimer	oligomeric_state	The results showed that the PGRMC1 dimer is not dissociated into monomer at all concentrations examined (Supplementary Fig. 11, lower panel), suggesting that the Kd value of haem-mediated dimer of PGRMC1 is under 3.5 μmol l−1.	RESULTS
65	72	monomer	oligomeric_state	The results showed that the PGRMC1 dimer is not dissociated into monomer at all concentrations examined (Supplementary Fig. 11, lower panel), suggesting that the Kd value of haem-mediated dimer of PGRMC1 is under 3.5 μmol l−1.	RESULTS
162	164	Kd	evidence	The results showed that the PGRMC1 dimer is not dissociated into monomer at all concentrations examined (Supplementary Fig. 11, lower panel), suggesting that the Kd value of haem-mediated dimer of PGRMC1 is under 3.5 μmol l−1.	RESULTS
174	178	haem	chemical	The results showed that the PGRMC1 dimer is not dissociated into monomer at all concentrations examined (Supplementary Fig. 11, lower panel), suggesting that the Kd value of haem-mediated dimer of PGRMC1 is under 3.5 μmol l−1.	RESULTS
188	193	dimer	oligomeric_state	The results showed that the PGRMC1 dimer is not dissociated into monomer at all concentrations examined (Supplementary Fig. 11, lower panel), suggesting that the Kd value of haem-mediated dimer of PGRMC1 is under 3.5 μmol l−1.	RESULTS
197	203	PGRMC1	protein	The results showed that the PGRMC1 dimer is not dissociated into monomer at all concentrations examined (Supplementary Fig. 11, lower panel), suggesting that the Kd value of haem-mediated dimer of PGRMC1 is under 3.5 μmol l−1.	RESULTS
38	44	PGRMC1	protein	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
45	50	dimer	oligomeric_state	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
77	83	dimers	oligomeric_state	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
87	107	extracellular domain	structure_element	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
111	128	membrane proteins	protein_type	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
137	157	Toll like receptor 9	protein	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
159	171	dimerization	oligomeric_state	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
172	174	Kd	evidence	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
202	220	plexin A2 receptor	protein	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
222	234	dimerization	oligomeric_state	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
235	237	Kd	evidence	A value of this kind implies that the PGRMC1 dimer is more stable than other dimers of extracellular domain of membrane proteins such as Toll like receptor 9 (dimerization Kd of 20 μmol l−1) (ref.) and plexin A2 receptor (dimerization Kd higher than 300 μmol l−1) (ref.).	RESULTS
43	46	apo	protein_state	The current analytical data confirmed that apo-PGRMC1 monomer converts into dimer by binding to haem in solution (Table 2).	RESULTS
47	53	PGRMC1	protein	The current analytical data confirmed that apo-PGRMC1 monomer converts into dimer by binding to haem in solution (Table 2).	RESULTS
54	61	monomer	oligomeric_state	The current analytical data confirmed that apo-PGRMC1 monomer converts into dimer by binding to haem in solution (Table 2).	RESULTS
76	81	dimer	oligomeric_state	The current analytical data confirmed that apo-PGRMC1 monomer converts into dimer by binding to haem in solution (Table 2).	RESULTS
96	100	haem	chemical	The current analytical data confirmed that apo-PGRMC1 monomer converts into dimer by binding to haem in solution (Table 2).	RESULTS
18	44	haem titration experiments	experimental_method	We also showed by haem titration experiments that haem binding to PGRMC1 was of low affinity with a Kd value of 50 nmol l−1; this is comparable with that of iron regulatory protein 2, which is known to be regulated by intracellular levels of haem (Fig. 2c and Supplementary Table 1).	RESULTS
50	54	haem	chemical	We also showed by haem titration experiments that haem binding to PGRMC1 was of low affinity with a Kd value of 50 nmol l−1; this is comparable with that of iron regulatory protein 2, which is known to be regulated by intracellular levels of haem (Fig. 2c and Supplementary Table 1).	RESULTS
66	72	PGRMC1	protein	We also showed by haem titration experiments that haem binding to PGRMC1 was of low affinity with a Kd value of 50 nmol l−1; this is comparable with that of iron regulatory protein 2, which is known to be regulated by intracellular levels of haem (Fig. 2c and Supplementary Table 1).	RESULTS
100	102	Kd	evidence	We also showed by haem titration experiments that haem binding to PGRMC1 was of low affinity with a Kd value of 50 nmol l−1; this is comparable with that of iron regulatory protein 2, which is known to be regulated by intracellular levels of haem (Fig. 2c and Supplementary Table 1).	RESULTS
157	182	iron regulatory protein 2	protein	We also showed by haem titration experiments that haem binding to PGRMC1 was of low affinity with a Kd value of 50 nmol l−1; this is comparable with that of iron regulatory protein 2, which is known to be regulated by intracellular levels of haem (Fig. 2c and Supplementary Table 1).	RESULTS
242	246	haem	chemical	We also showed by haem titration experiments that haem binding to PGRMC1 was of low affinity with a Kd value of 50 nmol l−1; this is comparable with that of iron regulatory protein 2, which is known to be regulated by intracellular levels of haem (Fig. 2c and Supplementary Table 1).	RESULTS
58	64	PGRMC1	protein	These results raised the possibility that the function of PGRMC1 is regulated by intracellular haem concentrations.	RESULTS
95	99	haem	chemical	These results raised the possibility that the function of PGRMC1 is regulated by intracellular haem concentrations.	RESULTS
0	2	CO	chemical	CO inhibits haem-dependent dimerization of PGRMC1	RESULTS
12	16	haem	chemical	CO inhibits haem-dependent dimerization of PGRMC1	RESULTS
27	39	dimerization	oligomeric_state	CO inhibits haem-dependent dimerization of PGRMC1	RESULTS
43	49	PGRMC1	protein	CO inhibits haem-dependent dimerization of PGRMC1	RESULTS
0	25	Crystallographic analyses	experimental_method	Crystallographic analyses revealed that Tyr113 of PGRMC1 is an axial ligand for haem and contributes to haem-dependent dimerization (Fig. 1a).	RESULTS
40	46	Tyr113	residue_name_number	Crystallographic analyses revealed that Tyr113 of PGRMC1 is an axial ligand for haem and contributes to haem-dependent dimerization (Fig. 1a).	RESULTS
50	56	PGRMC1	protein	Crystallographic analyses revealed that Tyr113 of PGRMC1 is an axial ligand for haem and contributes to haem-dependent dimerization (Fig. 1a).	RESULTS
80	84	haem	chemical	Crystallographic analyses revealed that Tyr113 of PGRMC1 is an axial ligand for haem and contributes to haem-dependent dimerization (Fig. 1a).	RESULTS
104	108	haem	chemical	Crystallographic analyses revealed that Tyr113 of PGRMC1 is an axial ligand for haem and contributes to haem-dependent dimerization (Fig. 1a).	RESULTS
119	131	dimerization	oligomeric_state	Crystallographic analyses revealed that Tyr113 of PGRMC1 is an axial ligand for haem and contributes to haem-dependent dimerization (Fig. 1a).	RESULTS
12	30	UV-visible spectra	evidence	Analysis of UV-visible spectra revealed that the heme of PGRMC1 is reducible from ferric to ferrous state, thus allowing CO binding (Fig. 3a).	RESULTS
49	53	heme	chemical	Analysis of UV-visible spectra revealed that the heme of PGRMC1 is reducible from ferric to ferrous state, thus allowing CO binding (Fig. 3a).	RESULTS
57	63	PGRMC1	protein	Analysis of UV-visible spectra revealed that the heme of PGRMC1 is reducible from ferric to ferrous state, thus allowing CO binding (Fig. 3a).	RESULTS
82	88	ferric	protein_state	Analysis of UV-visible spectra revealed that the heme of PGRMC1 is reducible from ferric to ferrous state, thus allowing CO binding (Fig. 3a).	RESULTS
92	99	ferrous	protein_state	Analysis of UV-visible spectra revealed that the heme of PGRMC1 is reducible from ferric to ferrous state, thus allowing CO binding (Fig. 3a).	RESULTS
121	123	CO	chemical	Analysis of UV-visible spectra revealed that the heme of PGRMC1 is reducible from ferric to ferrous state, thus allowing CO binding (Fig. 3a).	RESULTS
17	36	UV-visible spectrum	evidence	Furthermore, the UV-visible spectrum of the wild type PGRMC1 was the same as that of the C129S mutant of PGRMC1, and the R/Z ratio determined by the intensities between the Soret band (394 nm) peak and the 274-nm peak showed that these proteins were fully loaded with haem (Supplementary Fig. 12).	RESULTS
44	53	wild type	protein_state	Furthermore, the UV-visible spectrum of the wild type PGRMC1 was the same as that of the C129S mutant of PGRMC1, and the R/Z ratio determined by the intensities between the Soret band (394 nm) peak and the 274-nm peak showed that these proteins were fully loaded with haem (Supplementary Fig. 12).	RESULTS
54	60	PGRMC1	protein	Furthermore, the UV-visible spectrum of the wild type PGRMC1 was the same as that of the C129S mutant of PGRMC1, and the R/Z ratio determined by the intensities between the Soret band (394 nm) peak and the 274-nm peak showed that these proteins were fully loaded with haem (Supplementary Fig. 12).	RESULTS
89	94	C129S	mutant	Furthermore, the UV-visible spectrum of the wild type PGRMC1 was the same as that of the C129S mutant of PGRMC1, and the R/Z ratio determined by the intensities between the Soret band (394 nm) peak and the 274-nm peak showed that these proteins were fully loaded with haem (Supplementary Fig. 12).	RESULTS
95	101	mutant	protein_state	Furthermore, the UV-visible spectrum of the wild type PGRMC1 was the same as that of the C129S mutant of PGRMC1, and the R/Z ratio determined by the intensities between the Soret band (394 nm) peak and the 274-nm peak showed that these proteins were fully loaded with haem (Supplementary Fig. 12).	RESULTS
105	111	PGRMC1	protein	Furthermore, the UV-visible spectrum of the wild type PGRMC1 was the same as that of the C129S mutant of PGRMC1, and the R/Z ratio determined by the intensities between the Soret band (394 nm) peak and the 274-nm peak showed that these proteins were fully loaded with haem (Supplementary Fig. 12).	RESULTS
121	130	R/Z ratio	evidence	Furthermore, the UV-visible spectrum of the wild type PGRMC1 was the same as that of the C129S mutant of PGRMC1, and the R/Z ratio determined by the intensities between the Soret band (394 nm) peak and the 274-nm peak showed that these proteins were fully loaded with haem (Supplementary Fig. 12).	RESULTS
250	267	fully loaded with	protein_state	Furthermore, the UV-visible spectrum of the wild type PGRMC1 was the same as that of the C129S mutant of PGRMC1, and the R/Z ratio determined by the intensities between the Soret band (394 nm) peak and the 274-nm peak showed that these proteins were fully loaded with haem (Supplementary Fig. 12).	RESULTS
268	272	haem	chemical	Furthermore, the UV-visible spectrum of the wild type PGRMC1 was the same as that of the C129S mutant of PGRMC1, and the R/Z ratio determined by the intensities between the Soret band (394 nm) peak and the 274-nm peak showed that these proteins were fully loaded with haem (Supplementary Fig. 12).	RESULTS
16	22	ferric	protein_state	Analysis of the ferric form of PGRMC1 using resonance Raman spectroscopy (Supplementary Fig. 13) showed that the relative intensity of oxidation and spin state marker bands (ν4 and ν3) is close to 1.0, which is consistent with it being a haem protein with a proximal Tyr coordination.	RESULTS
31	37	PGRMC1	protein	Analysis of the ferric form of PGRMC1 using resonance Raman spectroscopy (Supplementary Fig. 13) showed that the relative intensity of oxidation and spin state marker bands (ν4 and ν3) is close to 1.0, which is consistent with it being a haem protein with a proximal Tyr coordination.	RESULTS
44	72	resonance Raman spectroscopy	experimental_method	Analysis of the ferric form of PGRMC1 using resonance Raman spectroscopy (Supplementary Fig. 13) showed that the relative intensity of oxidation and spin state marker bands (ν4 and ν3) is close to 1.0, which is consistent with it being a haem protein with a proximal Tyr coordination.	RESULTS
238	242	haem	chemical	Analysis of the ferric form of PGRMC1 using resonance Raman spectroscopy (Supplementary Fig. 13) showed that the relative intensity of oxidation and spin state marker bands (ν4 and ν3) is close to 1.0, which is consistent with it being a haem protein with a proximal Tyr coordination.	RESULTS
267	270	Tyr	residue_name	Analysis of the ferric form of PGRMC1 using resonance Raman spectroscopy (Supplementary Fig. 13) showed that the relative intensity of oxidation and spin state marker bands (ν4 and ν3) is close to 1.0, which is consistent with it being a haem protein with a proximal Tyr coordination.	RESULTS
11	22	Raman shift	evidence	A specific Raman shift peaking at vFe–CO=500 cm−1 demonstrated that the CO-bound haem of PGRMC1 is six-coordinated (Supplementary Fig. 13).	RESULTS
72	80	CO-bound	protein_state	A specific Raman shift peaking at vFe–CO=500 cm−1 demonstrated that the CO-bound haem of PGRMC1 is six-coordinated (Supplementary Fig. 13).	RESULTS
81	85	haem	chemical	A specific Raman shift peaking at vFe–CO=500 cm−1 demonstrated that the CO-bound haem of PGRMC1 is six-coordinated (Supplementary Fig. 13).	RESULTS
89	95	PGRMC1	protein	A specific Raman shift peaking at vFe–CO=500 cm−1 demonstrated that the CO-bound haem of PGRMC1 is six-coordinated (Supplementary Fig. 13).	RESULTS
6	12	PGRMC1	protein	Since PGRMC1 dimerization involves the open surface of haem on the opposite side of the axial Tyr113, no space for CO binding is available in the dimeric structure (Fig. 3b).	RESULTS
13	25	dimerization	oligomeric_state	Since PGRMC1 dimerization involves the open surface of haem on the opposite side of the axial Tyr113, no space for CO binding is available in the dimeric structure (Fig. 3b).	RESULTS
44	51	surface	site	Since PGRMC1 dimerization involves the open surface of haem on the opposite side of the axial Tyr113, no space for CO binding is available in the dimeric structure (Fig. 3b).	RESULTS
55	59	haem	chemical	Since PGRMC1 dimerization involves the open surface of haem on the opposite side of the axial Tyr113, no space for CO binding is available in the dimeric structure (Fig. 3b).	RESULTS
94	100	Tyr113	residue_name_number	Since PGRMC1 dimerization involves the open surface of haem on the opposite side of the axial Tyr113, no space for CO binding is available in the dimeric structure (Fig. 3b).	RESULTS
115	117	CO	chemical	Since PGRMC1 dimerization involves the open surface of haem on the opposite side of the axial Tyr113, no space for CO binding is available in the dimeric structure (Fig. 3b).	RESULTS
146	153	dimeric	oligomeric_state	Since PGRMC1 dimerization involves the open surface of haem on the opposite side of the axial Tyr113, no space for CO binding is available in the dimeric structure (Fig. 3b).	RESULTS
154	163	structure	evidence	Since PGRMC1 dimerization involves the open surface of haem on the opposite side of the axial Tyr113, no space for CO binding is available in the dimeric structure (Fig. 3b).	RESULTS
27	29	CO	chemical	This prompted us to ask if CO binding to haem causes dissociation of the PGRMC1 dimer.	RESULTS
41	45	haem	chemical	This prompted us to ask if CO binding to haem causes dissociation of the PGRMC1 dimer.	RESULTS
73	79	PGRMC1	protein	This prompted us to ask if CO binding to haem causes dissociation of the PGRMC1 dimer.	RESULTS
80	85	dimer	oligomeric_state	This prompted us to ask if CO binding to haem causes dissociation of the PGRMC1 dimer.	RESULTS
12	41	gel filtration chromatography	experimental_method	Analysis by gel filtration chromatography revealed that the relative molecular sizes of the wild-type and the C129S mutant of PGRMC1 are increased by adding haem to apo-PGRMC1 regardless of the oxidation state of the iron (Fig. 3c), which is in agreement with the results in Table 1.	RESULTS
92	101	wild-type	protein_state	Analysis by gel filtration chromatography revealed that the relative molecular sizes of the wild-type and the C129S mutant of PGRMC1 are increased by adding haem to apo-PGRMC1 regardless of the oxidation state of the iron (Fig. 3c), which is in agreement with the results in Table 1.	RESULTS
110	115	C129S	mutant	Analysis by gel filtration chromatography revealed that the relative molecular sizes of the wild-type and the C129S mutant of PGRMC1 are increased by adding haem to apo-PGRMC1 regardless of the oxidation state of the iron (Fig. 3c), which is in agreement with the results in Table 1.	RESULTS
116	122	mutant	protein_state	Analysis by gel filtration chromatography revealed that the relative molecular sizes of the wild-type and the C129S mutant of PGRMC1 are increased by adding haem to apo-PGRMC1 regardless of the oxidation state of the iron (Fig. 3c), which is in agreement with the results in Table 1.	RESULTS
126	132	PGRMC1	protein	Analysis by gel filtration chromatography revealed that the relative molecular sizes of the wild-type and the C129S mutant of PGRMC1 are increased by adding haem to apo-PGRMC1 regardless of the oxidation state of the iron (Fig. 3c), which is in agreement with the results in Table 1.	RESULTS
157	161	haem	chemical	Analysis by gel filtration chromatography revealed that the relative molecular sizes of the wild-type and the C129S mutant of PGRMC1 are increased by adding haem to apo-PGRMC1 regardless of the oxidation state of the iron (Fig. 3c), which is in agreement with the results in Table 1.	RESULTS
165	168	apo	protein_state	Analysis by gel filtration chromatography revealed that the relative molecular sizes of the wild-type and the C129S mutant of PGRMC1 are increased by adding haem to apo-PGRMC1 regardless of the oxidation state of the iron (Fig. 3c), which is in agreement with the results in Table 1.	RESULTS
169	175	PGRMC1	protein	Analysis by gel filtration chromatography revealed that the relative molecular sizes of the wild-type and the C129S mutant of PGRMC1 are increased by adding haem to apo-PGRMC1 regardless of the oxidation state of the iron (Fig. 3c), which is in agreement with the results in Table 1.	RESULTS
217	221	iron	chemical	Analysis by gel filtration chromatography revealed that the relative molecular sizes of the wild-type and the C129S mutant of PGRMC1 are increased by adding haem to apo-PGRMC1 regardless of the oxidation state of the iron (Fig. 3c), which is in agreement with the results in Table 1.	RESULTS
0	2	CO	chemical	CO application to ferrous PGRMC1 abolished the haem-dependent increase in its molecular size.	RESULTS
18	25	ferrous	protein_state	CO application to ferrous PGRMC1 abolished the haem-dependent increase in its molecular size.	RESULTS
26	32	PGRMC1	protein	CO application to ferrous PGRMC1 abolished the haem-dependent increase in its molecular size.	RESULTS
47	51	haem	chemical	CO application to ferrous PGRMC1 abolished the haem-dependent increase in its molecular size.	RESULTS
37	48	presence of	protein_state	Under this reducing condition in the presence of dithionite, analyses of UV-visible spectra indicated that CO-binding with haem-PGRMC1 is stable, showing only 20% reduction of the absorbance at 412 nm within 2 h (Supplementary Fig. 14).	RESULTS
49	59	dithionite	chemical	Under this reducing condition in the presence of dithionite, analyses of UV-visible spectra indicated that CO-binding with haem-PGRMC1 is stable, showing only 20% reduction of the absorbance at 412 nm within 2 h (Supplementary Fig. 14).	RESULTS
73	91	UV-visible spectra	evidence	Under this reducing condition in the presence of dithionite, analyses of UV-visible spectra indicated that CO-binding with haem-PGRMC1 is stable, showing only 20% reduction of the absorbance at 412 nm within 2 h (Supplementary Fig. 14).	RESULTS
107	109	CO	chemical	Under this reducing condition in the presence of dithionite, analyses of UV-visible spectra indicated that CO-binding with haem-PGRMC1 is stable, showing only 20% reduction of the absorbance at 412 nm within 2 h (Supplementary Fig. 14).	RESULTS
123	134	haem-PGRMC1	complex_assembly	Under this reducing condition in the presence of dithionite, analyses of UV-visible spectra indicated that CO-binding with haem-PGRMC1 is stable, showing only 20% reduction of the absorbance at 412 nm within 2 h (Supplementary Fig. 14).	RESULTS
138	144	stable	protein_state	Under this reducing condition in the presence of dithionite, analyses of UV-visible spectra indicated that CO-binding with haem-PGRMC1 is stable, showing only 20% reduction of the absorbance at 412 nm within 2 h (Supplementary Fig. 14).	RESULTS
17	26	Tyr113Phe	mutant	Furthermore, the Tyr113Phe (Y113F) mutant of PGRMC1 was not responsive to haem.	RESULTS
28	33	Y113F	mutant	Furthermore, the Tyr113Phe (Y113F) mutant of PGRMC1 was not responsive to haem.	RESULTS
35	41	mutant	protein_state	Furthermore, the Tyr113Phe (Y113F) mutant of PGRMC1 was not responsive to haem.	RESULTS
45	51	PGRMC1	protein	Furthermore, the Tyr113Phe (Y113F) mutant of PGRMC1 was not responsive to haem.	RESULTS
74	78	haem	chemical	Furthermore, the Tyr113Phe (Y113F) mutant of PGRMC1 was not responsive to haem.	RESULTS
27	29	CO	chemical	These results suggest that CO favours the six-coordinate form of haem and interferes with the haem-mediated dimerization of PGRMC1.	RESULTS
65	69	haem	chemical	These results suggest that CO favours the six-coordinate form of haem and interferes with the haem-mediated dimerization of PGRMC1.	RESULTS
94	98	haem	chemical	These results suggest that CO favours the six-coordinate form of haem and interferes with the haem-mediated dimerization of PGRMC1.	RESULTS
108	120	dimerization	oligomeric_state	These results suggest that CO favours the six-coordinate form of haem and interferes with the haem-mediated dimerization of PGRMC1.	RESULTS
124	130	PGRMC1	protein	These results suggest that CO favours the six-coordinate form of haem and interferes with the haem-mediated dimerization of PGRMC1.	RESULTS
37	39	CO	chemical	To examine the inhibitory effects of CO on haem-mediated PGRMC1 dimerization, SV-AUC analysis was carried out.	RESULTS
43	47	haem	chemical	To examine the inhibitory effects of CO on haem-mediated PGRMC1 dimerization, SV-AUC analysis was carried out.	RESULTS
57	63	PGRMC1	protein	To examine the inhibitory effects of CO on haem-mediated PGRMC1 dimerization, SV-AUC analysis was carried out.	RESULTS
64	76	dimerization	oligomeric_state	To examine the inhibitory effects of CO on haem-mediated PGRMC1 dimerization, SV-AUC analysis was carried out.	RESULTS
78	84	SV-AUC	experimental_method	To examine the inhibitory effects of CO on haem-mediated PGRMC1 dimerization, SV-AUC analysis was carried out.	RESULTS
30	34	haem	chemical	The peak corresponding to the haem/PGRMC1 dimer was detected under reducing conditions in the presence of dithionite (Supplementary Fig. 15, middle panel).	RESULTS
35	41	PGRMC1	protein	The peak corresponding to the haem/PGRMC1 dimer was detected under reducing conditions in the presence of dithionite (Supplementary Fig. 15, middle panel).	RESULTS
42	47	dimer	oligomeric_state	The peak corresponding to the haem/PGRMC1 dimer was detected under reducing conditions in the presence of dithionite (Supplementary Fig. 15, middle panel).	RESULTS
94	105	presence of	protein_state	The peak corresponding to the haem/PGRMC1 dimer was detected under reducing conditions in the presence of dithionite (Supplementary Fig. 15, middle panel).	RESULTS
106	116	dithionite	chemical	The peak corresponding to the haem/PGRMC1 dimer was detected under reducing conditions in the presence of dithionite (Supplementary Fig. 15, middle panel).	RESULTS
27	29	CO	chemical	Under these circumstances, CO application induced dissociation of the haem-mediated dimers of PGRMC1 to generate a peak of monomers (Supplementary Fig. 15, lower panel).	RESULTS
70	74	haem	chemical	Under these circumstances, CO application induced dissociation of the haem-mediated dimers of PGRMC1 to generate a peak of monomers (Supplementary Fig. 15, lower panel).	RESULTS
84	90	dimers	oligomeric_state	Under these circumstances, CO application induced dissociation of the haem-mediated dimers of PGRMC1 to generate a peak of monomers (Supplementary Fig. 15, lower panel).	RESULTS
94	100	PGRMC1	protein	Under these circumstances, CO application induced dissociation of the haem-mediated dimers of PGRMC1 to generate a peak of monomers (Supplementary Fig. 15, lower panel).	RESULTS
123	131	monomers	oligomeric_state	Under these circumstances, CO application induced dissociation of the haem-mediated dimers of PGRMC1 to generate a peak of monomers (Supplementary Fig. 15, lower panel).	RESULTS
76	82	PGRMC1	protein	These observations raised the transition model for structural regulation of PGRMC1 in response to haem (Fig. 3d).	RESULTS
98	102	haem	chemical	These observations raised the transition model for structural regulation of PGRMC1 in response to haem (Fig. 3d).	RESULTS
20	23	apo	protein_state	As mentioned above, apo-PGRMC1 exists as monomer.	RESULTS
24	30	PGRMC1	protein	As mentioned above, apo-PGRMC1 exists as monomer.	RESULTS
41	48	monomer	oligomeric_state	As mentioned above, apo-PGRMC1 exists as monomer.	RESULTS
16	20	haem	chemical	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
30	32	Kd	evidence	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
47	53	PGRMC1	protein	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
62	68	stable	protein_state	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
69	74	dimer	oligomeric_state	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
76	88	dimerization	oligomeric_state	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
89	91	Kd	evidence	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
115	123	stacking	bond_interaction	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
140	148	surfaces	site	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
173	177	haem	chemical	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
196	203	monomer	oligomeric_state	By binding with haem (binding Kd=50 nmol l−1), PGRMC1 forms a stable dimer (dimerization Kd<<3.5 μmol l−1) through stacking of the two open surfaces of the five-coordinated haem molecules in each monomer.	RESULTS
0	2	CO	chemical	CO induces the dissociation of the haem-mediated dimer of PGRMC1 by interfering with the haem-stacking interface via formation of the six-coordinated CO-haem-PGRMC1 complex.	RESULTS
35	39	haem	chemical	CO induces the dissociation of the haem-mediated dimer of PGRMC1 by interfering with the haem-stacking interface via formation of the six-coordinated CO-haem-PGRMC1 complex.	RESULTS
49	54	dimer	oligomeric_state	CO induces the dissociation of the haem-mediated dimer of PGRMC1 by interfering with the haem-stacking interface via formation of the six-coordinated CO-haem-PGRMC1 complex.	RESULTS
58	64	PGRMC1	protein	CO induces the dissociation of the haem-mediated dimer of PGRMC1 by interfering with the haem-stacking interface via formation of the six-coordinated CO-haem-PGRMC1 complex.	RESULTS
89	112	haem-stacking interface	site	CO induces the dissociation of the haem-mediated dimer of PGRMC1 by interfering with the haem-stacking interface via formation of the six-coordinated CO-haem-PGRMC1 complex.	RESULTS
150	164	CO-haem-PGRMC1	complex_assembly	CO induces the dissociation of the haem-mediated dimer of PGRMC1 by interfering with the haem-stacking interface via formation of the six-coordinated CO-haem-PGRMC1 complex.	RESULTS
81	87	PGRMC1	protein	Such a dynamic structural regulation led us to further examine the regulation of PGRMC1 functions in cancer cells.	RESULTS
0	6	PGRMC1	protein	PGRMC1 dimerization is required for binding to EGFR	RESULTS
7	19	dimerization	oligomeric_state	PGRMC1 dimerization is required for binding to EGFR	RESULTS
47	51	EGFR	protein_type	PGRMC1 dimerization is required for binding to EGFR	RESULTS
8	14	PGRMC1	protein	Because PGRMC1 is known to interact with EGFR and to accelerate tumour progression, we examined the effect of haem-dependent dimerization of PGRMC1 on its interaction with EGFR by using purified proteins.	RESULTS
41	45	EGFR	protein_type	Because PGRMC1 is known to interact with EGFR and to accelerate tumour progression, we examined the effect of haem-dependent dimerization of PGRMC1 on its interaction with EGFR by using purified proteins.	RESULTS
110	114	haem	chemical	Because PGRMC1 is known to interact with EGFR and to accelerate tumour progression, we examined the effect of haem-dependent dimerization of PGRMC1 on its interaction with EGFR by using purified proteins.	RESULTS
125	137	dimerization	oligomeric_state	Because PGRMC1 is known to interact with EGFR and to accelerate tumour progression, we examined the effect of haem-dependent dimerization of PGRMC1 on its interaction with EGFR by using purified proteins.	RESULTS
141	147	PGRMC1	protein	Because PGRMC1 is known to interact with EGFR and to accelerate tumour progression, we examined the effect of haem-dependent dimerization of PGRMC1 on its interaction with EGFR by using purified proteins.	RESULTS
172	176	EGFR	protein_type	Because PGRMC1 is known to interact with EGFR and to accelerate tumour progression, we examined the effect of haem-dependent dimerization of PGRMC1 on its interaction with EGFR by using purified proteins.	RESULTS
25	41	cytosolic domain	structure_element	As shown in Fig. 4a, the cytosolic domain of wild-type PGRMC1, but not the Y113F mutant, interacted with purified EGFR in a haem-dependent manner.	RESULTS
45	54	wild-type	protein_state	As shown in Fig. 4a, the cytosolic domain of wild-type PGRMC1, but not the Y113F mutant, interacted with purified EGFR in a haem-dependent manner.	RESULTS
55	61	PGRMC1	protein	As shown in Fig. 4a, the cytosolic domain of wild-type PGRMC1, but not the Y113F mutant, interacted with purified EGFR in a haem-dependent manner.	RESULTS
75	80	Y113F	mutant	As shown in Fig. 4a, the cytosolic domain of wild-type PGRMC1, but not the Y113F mutant, interacted with purified EGFR in a haem-dependent manner.	RESULTS
81	87	mutant	protein_state	As shown in Fig. 4a, the cytosolic domain of wild-type PGRMC1, but not the Y113F mutant, interacted with purified EGFR in a haem-dependent manner.	RESULTS
114	118	EGFR	protein_type	As shown in Fig. 4a, the cytosolic domain of wild-type PGRMC1, but not the Y113F mutant, interacted with purified EGFR in a haem-dependent manner.	RESULTS
124	128	haem	chemical	As shown in Fig. 4a, the cytosolic domain of wild-type PGRMC1, but not the Y113F mutant, interacted with purified EGFR in a haem-dependent manner.	RESULTS
38	47	ruthenium	chemical	This interaction was disrupted by the ruthenium-based CO-releasing molecule, CORM3, but not by RuCl3 as a control reagent (Fig. 4b).	RESULTS
54	56	CO	chemical	This interaction was disrupted by the ruthenium-based CO-releasing molecule, CORM3, but not by RuCl3 as a control reagent (Fig. 4b).	RESULTS
77	82	CORM3	chemical	This interaction was disrupted by the ruthenium-based CO-releasing molecule, CORM3, but not by RuCl3 as a control reagent (Fig. 4b).	RESULTS
95	100	RuCl3	chemical	This interaction was disrupted by the ruthenium-based CO-releasing molecule, CORM3, but not by RuCl3 as a control reagent (Fig. 4b).	RESULTS
58	64	PGRMC1	protein	We further analysed the intracellular interaction between PGRMC1 and EGFR.	RESULTS
69	73	EGFR	protein_type	We further analysed the intracellular interaction between PGRMC1 and EGFR.	RESULTS
0	11	FLAG-tagged	protein_state	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
12	18	PGRMC1	protein	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
19	40	ectopically expressed	experimental_method	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
44	49	human	species	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
80	98	immunoprecipitated	experimental_method	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
128	149	co-immunoprecipitated	experimental_method	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
150	154	EGFR	protein_type	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
159	169	endogenous	protein_state	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
170	176	PGRMC1	protein	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
193	199	PGRMC1	protein	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
217	233	Western blotting	experimental_method	FLAG-tagged PGRMC1 ectopically expressed in human colon cancer HCT116 cells was immunoprecipitated with anti-FLAG antibody, and co-immunoprecipitated EGFR and endogenous PGRMC1 binding to FLAG-PGRMC1 were detected by Western blotting (Fig. 4c).	RESULTS
4	9	C129S	mutant	The C129S mutant of PGRMC1 also interacted with endogenous PGRMC1 and EGFR (Supplementary Fig. 16).	RESULTS
10	16	mutant	protein_state	The C129S mutant of PGRMC1 also interacted with endogenous PGRMC1 and EGFR (Supplementary Fig. 16).	RESULTS
20	26	PGRMC1	protein	The C129S mutant of PGRMC1 also interacted with endogenous PGRMC1 and EGFR (Supplementary Fig. 16).	RESULTS
48	58	endogenous	protein_state	The C129S mutant of PGRMC1 also interacted with endogenous PGRMC1 and EGFR (Supplementary Fig. 16).	RESULTS
59	65	PGRMC1	protein	The C129S mutant of PGRMC1 also interacted with endogenous PGRMC1 and EGFR (Supplementary Fig. 16).	RESULTS
70	74	EGFR	protein_type	The C129S mutant of PGRMC1 also interacted with endogenous PGRMC1 and EGFR (Supplementary Fig. 16).	RESULTS
8	19	FLAG-tagged	protein_state	Whereas FLAG-tagged wild-type PGRMC1 interacted with endogenous PGRMC1 and EGFR, the Y113F mutant did not.	RESULTS
20	29	wild-type	protein_state	Whereas FLAG-tagged wild-type PGRMC1 interacted with endogenous PGRMC1 and EGFR, the Y113F mutant did not.	RESULTS
30	36	PGRMC1	protein	Whereas FLAG-tagged wild-type PGRMC1 interacted with endogenous PGRMC1 and EGFR, the Y113F mutant did not.	RESULTS
53	63	endogenous	protein_state	Whereas FLAG-tagged wild-type PGRMC1 interacted with endogenous PGRMC1 and EGFR, the Y113F mutant did not.	RESULTS
64	70	PGRMC1	protein	Whereas FLAG-tagged wild-type PGRMC1 interacted with endogenous PGRMC1 and EGFR, the Y113F mutant did not.	RESULTS
75	79	EGFR	protein_type	Whereas FLAG-tagged wild-type PGRMC1 interacted with endogenous PGRMC1 and EGFR, the Y113F mutant did not.	RESULTS
85	90	Y113F	mutant	Whereas FLAG-tagged wild-type PGRMC1 interacted with endogenous PGRMC1 and EGFR, the Y113F mutant did not.	RESULTS
91	97	mutant	protein_state	Whereas FLAG-tagged wild-type PGRMC1 interacted with endogenous PGRMC1 and EGFR, the Y113F mutant did not.	RESULTS
31	46	succinylacetone	chemical	We also examined the effect of succinylacetone (SA), an inhibitor of haem biosynthesis (Fig. 4d).	RESULTS
48	50	SA	chemical	We also examined the effect of succinylacetone (SA), an inhibitor of haem biosynthesis (Fig. 4d).	RESULTS
69	73	haem	chemical	We also examined the effect of succinylacetone (SA), an inhibitor of haem biosynthesis (Fig. 4d).	RESULTS
13	15	SA	chemical	As expected, SA significantly reduced PGRMC1 dimerization and its interaction with EGFR (Fig. 4e), indicating that haem-mediated dimerization of PGMRC1 is critical for its binding to EGFR.	RESULTS
30	37	reduced	protein_state	As expected, SA significantly reduced PGRMC1 dimerization and its interaction with EGFR (Fig. 4e), indicating that haem-mediated dimerization of PGMRC1 is critical for its binding to EGFR.	RESULTS
38	44	PGRMC1	protein	As expected, SA significantly reduced PGRMC1 dimerization and its interaction with EGFR (Fig. 4e), indicating that haem-mediated dimerization of PGMRC1 is critical for its binding to EGFR.	RESULTS
45	57	dimerization	oligomeric_state	As expected, SA significantly reduced PGRMC1 dimerization and its interaction with EGFR (Fig. 4e), indicating that haem-mediated dimerization of PGMRC1 is critical for its binding to EGFR.	RESULTS
83	87	EGFR	protein_type	As expected, SA significantly reduced PGRMC1 dimerization and its interaction with EGFR (Fig. 4e), indicating that haem-mediated dimerization of PGMRC1 is critical for its binding to EGFR.	RESULTS
115	119	haem	chemical	As expected, SA significantly reduced PGRMC1 dimerization and its interaction with EGFR (Fig. 4e), indicating that haem-mediated dimerization of PGMRC1 is critical for its binding to EGFR.	RESULTS
129	141	dimerization	oligomeric_state	As expected, SA significantly reduced PGRMC1 dimerization and its interaction with EGFR (Fig. 4e), indicating that haem-mediated dimerization of PGMRC1 is critical for its binding to EGFR.	RESULTS
145	151	PGMRC1	protein	As expected, SA significantly reduced PGRMC1 dimerization and its interaction with EGFR (Fig. 4e), indicating that haem-mediated dimerization of PGMRC1 is critical for its binding to EGFR.	RESULTS
183	187	EGFR	protein_type	As expected, SA significantly reduced PGRMC1 dimerization and its interaction with EGFR (Fig. 4e), indicating that haem-mediated dimerization of PGMRC1 is critical for its binding to EGFR.	RESULTS
0	6	PGRMC1	protein	PGRMC1 dimer facilitates EGFR-mediated cancer growth	RESULTS
7	12	dimer	oligomeric_state	PGRMC1 dimer facilitates EGFR-mediated cancer growth	RESULTS
25	29	EGFR	protein_type	PGRMC1 dimer facilitates EGFR-mediated cancer growth	RESULTS
53	59	PGRMC1	protein	Next, we investigated the functional significance of PGRMC1 dimerization in EGFR signaling.	RESULTS
60	72	dimerization	oligomeric_state	Next, we investigated the functional significance of PGRMC1 dimerization in EGFR signaling.	RESULTS
76	80	EGFR	protein_type	Next, we investigated the functional significance of PGRMC1 dimerization in EGFR signaling.	RESULTS
0	3	EGF	protein_type	EGF-induced phosphorylations of EGFR and its downstream targets AKT and ERK were decreased by PGRMC1 knockdown (PGRMC1-KD) (Fig. 4f).	RESULTS
12	28	phosphorylations	ptm	EGF-induced phosphorylations of EGFR and its downstream targets AKT and ERK were decreased by PGRMC1 knockdown (PGRMC1-KD) (Fig. 4f).	RESULTS
32	36	EGFR	protein_type	EGF-induced phosphorylations of EGFR and its downstream targets AKT and ERK were decreased by PGRMC1 knockdown (PGRMC1-KD) (Fig. 4f).	RESULTS
64	67	AKT	protein_type	EGF-induced phosphorylations of EGFR and its downstream targets AKT and ERK were decreased by PGRMC1 knockdown (PGRMC1-KD) (Fig. 4f).	RESULTS
72	75	ERK	protein_type	EGF-induced phosphorylations of EGFR and its downstream targets AKT and ERK were decreased by PGRMC1 knockdown (PGRMC1-KD) (Fig. 4f).	RESULTS
94	100	PGRMC1	protein	EGF-induced phosphorylations of EGFR and its downstream targets AKT and ERK were decreased by PGRMC1 knockdown (PGRMC1-KD) (Fig. 4f).	RESULTS
101	110	knockdown	protein_state	EGF-induced phosphorylations of EGFR and its downstream targets AKT and ERK were decreased by PGRMC1 knockdown (PGRMC1-KD) (Fig. 4f).	RESULTS
112	121	PGRMC1-KD	mutant	EGF-induced phosphorylations of EGFR and its downstream targets AKT and ERK were decreased by PGRMC1 knockdown (PGRMC1-KD) (Fig. 4f).	RESULTS
11	15	EGFR	protein_type	Similarly, EGFR signaling was suppressed by treatment of HCT116 cells with SA (Fig. 4g) or CORM3 (Fig. 4h).	RESULTS
75	77	SA	chemical	Similarly, EGFR signaling was suppressed by treatment of HCT116 cells with SA (Fig. 4g) or CORM3 (Fig. 4h).	RESULTS
91	96	CORM3	chemical	Similarly, EGFR signaling was suppressed by treatment of HCT116 cells with SA (Fig. 4g) or CORM3 (Fig. 4h).	RESULTS
29	33	haem	chemical	These results suggested that haem-mediated dimerization of PGRMC1 is critical for EGFR signaling.	RESULTS
43	55	dimerization	oligomeric_state	These results suggested that haem-mediated dimerization of PGRMC1 is critical for EGFR signaling.	RESULTS
59	65	PGRMC1	protein	These results suggested that haem-mediated dimerization of PGRMC1 is critical for EGFR signaling.	RESULTS
82	86	EGFR	protein_type	These results suggested that haem-mediated dimerization of PGRMC1 is critical for EGFR signaling.	RESULTS
39	48	dimerized	protein_state	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
57	63	PGRMC1	protein	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
102	108	PGRMC1	protein	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
109	137	knockdown-rescue experiments	experimental_method	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
144	155	FLAG-tagged	protein_state	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
156	165	wild-type	protein_state	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
170	175	Y113F	mutant	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
176	182	PGRMC1	protein	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
183	201	expression vectors	experimental_method	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
212	228	silent mutations	experimental_method	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
234	244	introduced	experimental_method	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
286	291	shRNA	chemical	To further investigate the role of the dimerized form of PGRMC1 in cancer proliferation, we performed PGRMC1 knockdown-rescue experiments using FLAG-tagged wild-type and Y113F PGRMC1 expression vectors, in which silent mutations were introduced into the nucleotide sequence targeted by shRNA (Fig. 5a).	RESULTS
56	69	knocking down	experimental_method	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
70	76	PGRMC1	protein	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
78	87	PGRMC1-KD	mutant	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
121	125	EGFR	protein_type	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
136	145	erlotinib	chemical	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
214	227	co-expression	experimental_method	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
231	246	shRNA-resistant	protein_state	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
247	256	wild-type	protein_state	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
257	263	PGRMC1	protein	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
279	284	Y113F	mutant	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
285	291	mutant	protein_state	While proliferation of HCT116 cells was not affected by knocking down PGRMC1, PGRMC1-KD cells were more sensitive to the EGFR inhibitor erlotinib than control HCT116 cells, and the knockdown effect was reversed by co-expression of shRNA-resistant wild-type PGRMC1 but not of the Y113F mutant (Fig. 5b).	RESULTS
46	52	shRNAs	chemical	Chemosensitivity enhancement by two different shRNAs to PGRMC1 was seen also in HCT116 cells and human hepatoma HuH7 cells (Supplementary Fig. 17).	RESULTS
56	62	PGRMC1	protein	Chemosensitivity enhancement by two different shRNAs to PGRMC1 was seen also in HCT116 cells and human hepatoma HuH7 cells (Supplementary Fig. 17).	RESULTS
97	102	human	species	Chemosensitivity enhancement by two different shRNAs to PGRMC1 was seen also in HCT116 cells and human hepatoma HuH7 cells (Supplementary Fig. 17).	RESULTS
13	22	PGRMC1-KD	mutant	Furthermore, PGRMC1-KD inhibited spheroid formation of HCT116 cells in culture, and this inhibition was reversed by co-expression of wild-type PGRMC1 but not of the Y113F mutant (Fig. 5c and Supplementary Fig. 18).	RESULTS
116	129	co-expression	experimental_method	Furthermore, PGRMC1-KD inhibited spheroid formation of HCT116 cells in culture, and this inhibition was reversed by co-expression of wild-type PGRMC1 but not of the Y113F mutant (Fig. 5c and Supplementary Fig. 18).	RESULTS
133	142	wild-type	protein_state	Furthermore, PGRMC1-KD inhibited spheroid formation of HCT116 cells in culture, and this inhibition was reversed by co-expression of wild-type PGRMC1 but not of the Y113F mutant (Fig. 5c and Supplementary Fig. 18).	RESULTS
143	149	PGRMC1	protein	Furthermore, PGRMC1-KD inhibited spheroid formation of HCT116 cells in culture, and this inhibition was reversed by co-expression of wild-type PGRMC1 but not of the Y113F mutant (Fig. 5c and Supplementary Fig. 18).	RESULTS
165	170	Y113F	mutant	Furthermore, PGRMC1-KD inhibited spheroid formation of HCT116 cells in culture, and this inhibition was reversed by co-expression of wild-type PGRMC1 but not of the Y113F mutant (Fig. 5c and Supplementary Fig. 18).	RESULTS
171	177	mutant	protein_state	Furthermore, PGRMC1-KD inhibited spheroid formation of HCT116 cells in culture, and this inhibition was reversed by co-expression of wild-type PGRMC1 but not of the Y113F mutant (Fig. 5c and Supplementary Fig. 18).	RESULTS
6	12	PGRMC1	protein	Thus, PGRMC1 dimerization is important for cancer cell proliferation and chemoresistance.	RESULTS
13	25	dimerization	oligomeric_state	Thus, PGRMC1 dimerization is important for cancer cell proliferation and chemoresistance.	RESULTS
24	30	PGRMC1	protein	We examined the role of PGRMC1 in metastatic progression by xenograft transplantation assays using super-immunodeficient NOD/scid/γnull (NOG) mice.	RESULTS
60	92	xenograft transplantation assays	experimental_method	We examined the role of PGRMC1 in metastatic progression by xenograft transplantation assays using super-immunodeficient NOD/scid/γnull (NOG) mice.	RESULTS
15	41	intra-splenic implantation	experimental_method	Ten days after intra-splenic implantation of HCT116 cells that were genetically tagged with a fluorescent protein Venus, the group implanted with PGRMC1-KD cells showed a significant decrease of liver metastasis in comparison with the control group (Fig. 5d).	RESULTS
146	155	PGRMC1-KD	mutant	Ten days after intra-splenic implantation of HCT116 cells that were genetically tagged with a fluorescent protein Venus, the group implanted with PGRMC1-KD cells showed a significant decrease of liver metastasis in comparison with the control group (Fig. 5d).	RESULTS
15	21	PGRMC1	protein	Interaction of PGRMC1 dimer with cytochromes P450	RESULTS
22	27	dimer	oligomeric_state	Interaction of PGRMC1 dimer with cytochromes P450	RESULTS
33	49	cytochromes P450	protein_type	Interaction of PGRMC1 dimer with cytochromes P450	RESULTS
6	12	PGRMC1	protein	Since PGRMC1 has been shown to interact with cytochromes P450 (ref), we investigated whether the haem-mediated dimerization of PGRMC1 is necessary for their interactions.	RESULTS
45	61	cytochromes P450	protein_type	Since PGRMC1 has been shown to interact with cytochromes P450 (ref), we investigated whether the haem-mediated dimerization of PGRMC1 is necessary for their interactions.	RESULTS
97	101	haem	chemical	Since PGRMC1 has been shown to interact with cytochromes P450 (ref), we investigated whether the haem-mediated dimerization of PGRMC1 is necessary for their interactions.	RESULTS
111	123	dimerization	oligomeric_state	Since PGRMC1 has been shown to interact with cytochromes P450 (ref), we investigated whether the haem-mediated dimerization of PGRMC1 is necessary for their interactions.	RESULTS
127	133	PGRMC1	protein	Since PGRMC1 has been shown to interact with cytochromes P450 (ref), we investigated whether the haem-mediated dimerization of PGRMC1 is necessary for their interactions.	RESULTS
12	18	CYP1A2	protein	Recombinant CYP1A2 and CYP3A4 including a microsomal formulation containing cytochrome b5 and cytochrome P450 reductase, drug-metabolizing cytochromes P450, interacted with wild-type PGRMC1, but not with the Y113F mutant, in a haem-dependent manner (Fig. 6a,b).	RESULTS
23	29	CYP3A4	protein	Recombinant CYP1A2 and CYP3A4 including a microsomal formulation containing cytochrome b5 and cytochrome P450 reductase, drug-metabolizing cytochromes P450, interacted with wild-type PGRMC1, but not with the Y113F mutant, in a haem-dependent manner (Fig. 6a,b).	RESULTS
76	89	cytochrome b5	protein_type	Recombinant CYP1A2 and CYP3A4 including a microsomal formulation containing cytochrome b5 and cytochrome P450 reductase, drug-metabolizing cytochromes P450, interacted with wild-type PGRMC1, but not with the Y113F mutant, in a haem-dependent manner (Fig. 6a,b).	RESULTS
94	119	cytochrome P450 reductase	protein	Recombinant CYP1A2 and CYP3A4 including a microsomal formulation containing cytochrome b5 and cytochrome P450 reductase, drug-metabolizing cytochromes P450, interacted with wild-type PGRMC1, but not with the Y113F mutant, in a haem-dependent manner (Fig. 6a,b).	RESULTS
139	155	cytochromes P450	protein_type	Recombinant CYP1A2 and CYP3A4 including a microsomal formulation containing cytochrome b5 and cytochrome P450 reductase, drug-metabolizing cytochromes P450, interacted with wild-type PGRMC1, but not with the Y113F mutant, in a haem-dependent manner (Fig. 6a,b).	RESULTS
173	182	wild-type	protein_state	Recombinant CYP1A2 and CYP3A4 including a microsomal formulation containing cytochrome b5 and cytochrome P450 reductase, drug-metabolizing cytochromes P450, interacted with wild-type PGRMC1, but not with the Y113F mutant, in a haem-dependent manner (Fig. 6a,b).	RESULTS
183	189	PGRMC1	protein	Recombinant CYP1A2 and CYP3A4 including a microsomal formulation containing cytochrome b5 and cytochrome P450 reductase, drug-metabolizing cytochromes P450, interacted with wild-type PGRMC1, but not with the Y113F mutant, in a haem-dependent manner (Fig. 6a,b).	RESULTS
208	213	Y113F	mutant	Recombinant CYP1A2 and CYP3A4 including a microsomal formulation containing cytochrome b5 and cytochrome P450 reductase, drug-metabolizing cytochromes P450, interacted with wild-type PGRMC1, but not with the Y113F mutant, in a haem-dependent manner (Fig. 6a,b).	RESULTS
214	220	mutant	protein_state	Recombinant CYP1A2 and CYP3A4 including a microsomal formulation containing cytochrome b5 and cytochrome P450 reductase, drug-metabolizing cytochromes P450, interacted with wild-type PGRMC1, but not with the Y113F mutant, in a haem-dependent manner (Fig. 6a,b).	RESULTS
227	231	haem	chemical	Recombinant CYP1A2 and CYP3A4 including a microsomal formulation containing cytochrome b5 and cytochrome P450 reductase, drug-metabolizing cytochromes P450, interacted with wild-type PGRMC1, but not with the Y113F mutant, in a haem-dependent manner (Fig. 6a,b).	RESULTS
29	35	PGRMC1	protein	Moreover, the interaction of PGRMC1 with CYP1A2 was blocked by CORM3 under reducing conditions (Fig. 6c), indicating that PGRMC1 dimerization is necessary for its interaction with cytochromes P450.	RESULTS
41	47	CYP1A2	protein	Moreover, the interaction of PGRMC1 with CYP1A2 was blocked by CORM3 under reducing conditions (Fig. 6c), indicating that PGRMC1 dimerization is necessary for its interaction with cytochromes P450.	RESULTS
63	68	CORM3	chemical	Moreover, the interaction of PGRMC1 with CYP1A2 was blocked by CORM3 under reducing conditions (Fig. 6c), indicating that PGRMC1 dimerization is necessary for its interaction with cytochromes P450.	RESULTS
122	128	PGRMC1	protein	Moreover, the interaction of PGRMC1 with CYP1A2 was blocked by CORM3 under reducing conditions (Fig. 6c), indicating that PGRMC1 dimerization is necessary for its interaction with cytochromes P450.	RESULTS
129	141	dimerization	oligomeric_state	Moreover, the interaction of PGRMC1 with CYP1A2 was blocked by CORM3 under reducing conditions (Fig. 6c), indicating that PGRMC1 dimerization is necessary for its interaction with cytochromes P450.	RESULTS
180	196	cytochromes P450	protein_type	Moreover, the interaction of PGRMC1 with CYP1A2 was blocked by CORM3 under reducing conditions (Fig. 6c), indicating that PGRMC1 dimerization is necessary for its interaction with cytochromes P450.	RESULTS
0	11	Doxorubicin	chemical	Doxorubicin is an anti-cancer reagent that is metabolized into inactive doxorubicinol by CYP2D6 and CYP3A4 (Fig. 6d).	RESULTS
72	85	doxorubicinol	chemical	Doxorubicin is an anti-cancer reagent that is metabolized into inactive doxorubicinol by CYP2D6 and CYP3A4 (Fig. 6d).	RESULTS
89	95	CYP2D6	protein	Doxorubicin is an anti-cancer reagent that is metabolized into inactive doxorubicinol by CYP2D6 and CYP3A4 (Fig. 6d).	RESULTS
100	106	CYP3A4	protein	Doxorubicin is an anti-cancer reagent that is metabolized into inactive doxorubicinol by CYP2D6 and CYP3A4 (Fig. 6d).	RESULTS
0	9	PGRMC1-KD	mutant	PGRMC1-KD significantly suppressed the conversion of doxorubicin to doxorubicinol (Fig. 6d) and increased sensitivity to doxorubicin (Fig. 6e).	RESULTS
53	64	doxorubicin	chemical	PGRMC1-KD significantly suppressed the conversion of doxorubicin to doxorubicinol (Fig. 6d) and increased sensitivity to doxorubicin (Fig. 6e).	RESULTS
68	81	doxorubicinol	chemical	PGRMC1-KD significantly suppressed the conversion of doxorubicin to doxorubicinol (Fig. 6d) and increased sensitivity to doxorubicin (Fig. 6e).	RESULTS
121	132	doxorubicin	chemical	PGRMC1-KD significantly suppressed the conversion of doxorubicin to doxorubicinol (Fig. 6d) and increased sensitivity to doxorubicin (Fig. 6e).	RESULTS
9	20	doxorubicin	chemical	Enhanced doxorubicin sensitivity was modestly but significantly induced by PGRMC1-KD.	RESULTS
75	84	PGRMC1-KD	mutant	Enhanced doxorubicin sensitivity was modestly but significantly induced by PGRMC1-KD.	RESULTS
28	41	co-expression	experimental_method	This effect was reversed by co-expression of the wild-type PGRMC1 but not of the Y113F mutant, suggesting that PGRMC1 enhances doxorubicin resistance of cancer cells by facilitating its degradation via cytochromes P450.	RESULTS
49	58	wild-type	protein_state	This effect was reversed by co-expression of the wild-type PGRMC1 but not of the Y113F mutant, suggesting that PGRMC1 enhances doxorubicin resistance of cancer cells by facilitating its degradation via cytochromes P450.	RESULTS
59	65	PGRMC1	protein	This effect was reversed by co-expression of the wild-type PGRMC1 but not of the Y113F mutant, suggesting that PGRMC1 enhances doxorubicin resistance of cancer cells by facilitating its degradation via cytochromes P450.	RESULTS
81	86	Y113F	mutant	This effect was reversed by co-expression of the wild-type PGRMC1 but not of the Y113F mutant, suggesting that PGRMC1 enhances doxorubicin resistance of cancer cells by facilitating its degradation via cytochromes P450.	RESULTS
87	93	mutant	protein_state	This effect was reversed by co-expression of the wild-type PGRMC1 but not of the Y113F mutant, suggesting that PGRMC1 enhances doxorubicin resistance of cancer cells by facilitating its degradation via cytochromes P450.	RESULTS
111	117	PGRMC1	protein	This effect was reversed by co-expression of the wild-type PGRMC1 but not of the Y113F mutant, suggesting that PGRMC1 enhances doxorubicin resistance of cancer cells by facilitating its degradation via cytochromes P450.	RESULTS
127	138	doxorubicin	chemical	This effect was reversed by co-expression of the wild-type PGRMC1 but not of the Y113F mutant, suggesting that PGRMC1 enhances doxorubicin resistance of cancer cells by facilitating its degradation via cytochromes P450.	RESULTS
202	218	cytochromes P450	protein_type	This effect was reversed by co-expression of the wild-type PGRMC1 but not of the Y113F mutant, suggesting that PGRMC1 enhances doxorubicin resistance of cancer cells by facilitating its degradation via cytochromes P450.	RESULTS
53	59	PGRMC1	protein	To gain further insight into the interaction between PGRMC1 and cytochromes P450, surface plasmon resonance analyses were conducted using recombinant CYP51 and PGRMC1.	RESULTS
64	80	cytochromes P450	protein_type	To gain further insight into the interaction between PGRMC1 and cytochromes P450, surface plasmon resonance analyses were conducted using recombinant CYP51 and PGRMC1.	RESULTS
82	116	surface plasmon resonance analyses	experimental_method	To gain further insight into the interaction between PGRMC1 and cytochromes P450, surface plasmon resonance analyses were conducted using recombinant CYP51 and PGRMC1.	RESULTS
150	155	CYP51	protein	To gain further insight into the interaction between PGRMC1 and cytochromes P450, surface plasmon resonance analyses were conducted using recombinant CYP51 and PGRMC1.	RESULTS
160	166	PGRMC1	protein	To gain further insight into the interaction between PGRMC1 and cytochromes P450, surface plasmon resonance analyses were conducted using recombinant CYP51 and PGRMC1.	RESULTS
48	54	PGRMC1	protein	This was based on a previous study showing that PGRMC1 binds to CYP51 and enhances cholesterol biosynthesis by CYP51 (refs).	RESULTS
64	69	CYP51	protein	This was based on a previous study showing that PGRMC1 binds to CYP51 and enhances cholesterol biosynthesis by CYP51 (refs).	RESULTS
111	116	CYP51	protein	This was based on a previous study showing that PGRMC1 binds to CYP51 and enhances cholesterol biosynthesis by CYP51 (refs).	RESULTS
0	5	CYP51	protein	CYP51 interacted with PGRMC1 in a concentration-dependent manner in the presence of haem, but not in its absence (Supplementary Fig. 19), suggesting the requirement for the haem-dependent dimerization of PGRMC1.	RESULTS
22	28	PGRMC1	protein	CYP51 interacted with PGRMC1 in a concentration-dependent manner in the presence of haem, but not in its absence (Supplementary Fig. 19), suggesting the requirement for the haem-dependent dimerization of PGRMC1.	RESULTS
72	83	presence of	protein_state	CYP51 interacted with PGRMC1 in a concentration-dependent manner in the presence of haem, but not in its absence (Supplementary Fig. 19), suggesting the requirement for the haem-dependent dimerization of PGRMC1.	RESULTS
84	88	haem	chemical	CYP51 interacted with PGRMC1 in a concentration-dependent manner in the presence of haem, but not in its absence (Supplementary Fig. 19), suggesting the requirement for the haem-dependent dimerization of PGRMC1.	RESULTS
105	112	absence	protein_state	CYP51 interacted with PGRMC1 in a concentration-dependent manner in the presence of haem, but not in its absence (Supplementary Fig. 19), suggesting the requirement for the haem-dependent dimerization of PGRMC1.	RESULTS
173	177	haem	chemical	CYP51 interacted with PGRMC1 in a concentration-dependent manner in the presence of haem, but not in its absence (Supplementary Fig. 19), suggesting the requirement for the haem-dependent dimerization of PGRMC1.	RESULTS
188	200	dimerization	oligomeric_state	CYP51 interacted with PGRMC1 in a concentration-dependent manner in the presence of haem, but not in its absence (Supplementary Fig. 19), suggesting the requirement for the haem-dependent dimerization of PGRMC1.	RESULTS
204	210	PGRMC1	protein	CYP51 interacted with PGRMC1 in a concentration-dependent manner in the presence of haem, but not in its absence (Supplementary Fig. 19), suggesting the requirement for the haem-dependent dimerization of PGRMC1.	RESULTS
4	6	Kd	evidence	The Kd value of PGRMC1 binding to CYP51 was in a micromolar range and comparable with those of other haem proteins, such as cytochrome P450 reductase and neuroglobin/Gαi1 (ref.), suggesting that haem-dependent PGRMC1 interaction with CYP51 is biologically relevant.	RESULTS
16	22	PGRMC1	protein	The Kd value of PGRMC1 binding to CYP51 was in a micromolar range and comparable with those of other haem proteins, such as cytochrome P450 reductase and neuroglobin/Gαi1 (ref.), suggesting that haem-dependent PGRMC1 interaction with CYP51 is biologically relevant.	RESULTS
34	39	CYP51	protein	The Kd value of PGRMC1 binding to CYP51 was in a micromolar range and comparable with those of other haem proteins, such as cytochrome P450 reductase and neuroglobin/Gαi1 (ref.), suggesting that haem-dependent PGRMC1 interaction with CYP51 is biologically relevant.	RESULTS
101	105	haem	chemical	The Kd value of PGRMC1 binding to CYP51 was in a micromolar range and comparable with those of other haem proteins, such as cytochrome P450 reductase and neuroglobin/Gαi1 (ref.), suggesting that haem-dependent PGRMC1 interaction with CYP51 is biologically relevant.	RESULTS
124	149	cytochrome P450 reductase	protein	The Kd value of PGRMC1 binding to CYP51 was in a micromolar range and comparable with those of other haem proteins, such as cytochrome P450 reductase and neuroglobin/Gαi1 (ref.), suggesting that haem-dependent PGRMC1 interaction with CYP51 is biologically relevant.	RESULTS
154	165	neuroglobin	protein	The Kd value of PGRMC1 binding to CYP51 was in a micromolar range and comparable with those of other haem proteins, such as cytochrome P450 reductase and neuroglobin/Gαi1 (ref.), suggesting that haem-dependent PGRMC1 interaction with CYP51 is biologically relevant.	RESULTS
166	170	Gαi1	protein	The Kd value of PGRMC1 binding to CYP51 was in a micromolar range and comparable with those of other haem proteins, such as cytochrome P450 reductase and neuroglobin/Gαi1 (ref.), suggesting that haem-dependent PGRMC1 interaction with CYP51 is biologically relevant.	RESULTS
195	199	haem	chemical	The Kd value of PGRMC1 binding to CYP51 was in a micromolar range and comparable with those of other haem proteins, such as cytochrome P450 reductase and neuroglobin/Gαi1 (ref.), suggesting that haem-dependent PGRMC1 interaction with CYP51 is biologically relevant.	RESULTS
210	216	PGRMC1	protein	The Kd value of PGRMC1 binding to CYP51 was in a micromolar range and comparable with those of other haem proteins, such as cytochrome P450 reductase and neuroglobin/Gαi1 (ref.), suggesting that haem-dependent PGRMC1 interaction with CYP51 is biologically relevant.	RESULTS
234	239	CYP51	protein	The Kd value of PGRMC1 binding to CYP51 was in a micromolar range and comparable with those of other haem proteins, such as cytochrome P450 reductase and neuroglobin/Gαi1 (ref.), suggesting that haem-dependent PGRMC1 interaction with CYP51 is biologically relevant.	RESULTS
30	36	PGRMC1	protein	In this study, we showed that PGRMC1 dimerizes by stacking interactions of haem molecules from each monomer.	DISCUSS
37	46	dimerizes	oligomeric_state	In this study, we showed that PGRMC1 dimerizes by stacking interactions of haem molecules from each monomer.	DISCUSS
50	71	stacking interactions	bond_interaction	In this study, we showed that PGRMC1 dimerizes by stacking interactions of haem molecules from each monomer.	DISCUSS
75	79	haem	chemical	In this study, we showed that PGRMC1 dimerizes by stacking interactions of haem molecules from each monomer.	DISCUSS
100	107	monomer	oligomeric_state	In this study, we showed that PGRMC1 dimerizes by stacking interactions of haem molecules from each monomer.	DISCUSS
37	78	translationally-controlled tumour protein	protein_type	Recently, Lucas et al. reported that translationally-controlled tumour protein was dimerized by binding with haem, but its structural basis remains unclear.	DISCUSS
83	92	dimerized	protein_state	Recently, Lucas et al. reported that translationally-controlled tumour protein was dimerized by binding with haem, but its structural basis remains unclear.	DISCUSS
109	113	haem	chemical	Recently, Lucas et al. reported that translationally-controlled tumour protein was dimerized by binding with haem, but its structural basis remains unclear.	DISCUSS
88	106	haem–haem stacking	bond_interaction	This is the report showing crystallographic evidence that indicates roles of the direct haem–haem stacking in haem-mediated dimerization in eukaryotes, although a few examples are known in bacteria.	DISCUSS
110	114	haem	chemical	This is the report showing crystallographic evidence that indicates roles of the direct haem–haem stacking in haem-mediated dimerization in eukaryotes, although a few examples are known in bacteria.	DISCUSS
124	136	dimerization	oligomeric_state	This is the report showing crystallographic evidence that indicates roles of the direct haem–haem stacking in haem-mediated dimerization in eukaryotes, although a few examples are known in bacteria.	DISCUSS
140	150	eukaryotes	taxonomy_domain	This is the report showing crystallographic evidence that indicates roles of the direct haem–haem stacking in haem-mediated dimerization in eukaryotes, although a few examples are known in bacteria.	DISCUSS
189	197	bacteria	taxonomy_domain	This is the report showing crystallographic evidence that indicates roles of the direct haem–haem stacking in haem-mediated dimerization in eukaryotes, although a few examples are known in bacteria.	DISCUSS
0	19	Sequence alignments	experimental_method	Sequence alignments show that haem-binding residues (Tyr113, Tyr107, Lys163 and Tyr164) in PGRMC1 are conserved among MAPR proteins (Supplementary Fig. 5).	DISCUSS
30	51	haem-binding residues	site	Sequence alignments show that haem-binding residues (Tyr113, Tyr107, Lys163 and Tyr164) in PGRMC1 are conserved among MAPR proteins (Supplementary Fig. 5).	DISCUSS
53	59	Tyr113	residue_name_number	Sequence alignments show that haem-binding residues (Tyr113, Tyr107, Lys163 and Tyr164) in PGRMC1 are conserved among MAPR proteins (Supplementary Fig. 5).	DISCUSS
61	67	Tyr107	residue_name_number	Sequence alignments show that haem-binding residues (Tyr113, Tyr107, Lys163 and Tyr164) in PGRMC1 are conserved among MAPR proteins (Supplementary Fig. 5).	DISCUSS
69	75	Lys163	residue_name_number	Sequence alignments show that haem-binding residues (Tyr113, Tyr107, Lys163 and Tyr164) in PGRMC1 are conserved among MAPR proteins (Supplementary Fig. 5).	DISCUSS
80	86	Tyr164	residue_name_number	Sequence alignments show that haem-binding residues (Tyr113, Tyr107, Lys163 and Tyr164) in PGRMC1 are conserved among MAPR proteins (Supplementary Fig. 5).	DISCUSS
91	97	PGRMC1	protein	Sequence alignments show that haem-binding residues (Tyr113, Tyr107, Lys163 and Tyr164) in PGRMC1 are conserved among MAPR proteins (Supplementary Fig. 5).	DISCUSS
102	111	conserved	protein_state	Sequence alignments show that haem-binding residues (Tyr113, Tyr107, Lys163 and Tyr164) in PGRMC1 are conserved among MAPR proteins (Supplementary Fig. 5).	DISCUSS
118	122	MAPR	protein_type	Sequence alignments show that haem-binding residues (Tyr113, Tyr107, Lys163 and Tyr164) in PGRMC1 are conserved among MAPR proteins (Supplementary Fig. 5).	DISCUSS
26	30	Y113	residue_name_number	In the current study, the Y113 residue plays a crucial role for the haem-dependent dimerization of PGRMC1 and resultant regulation of cancer proliferation and chemoresistance (Figs 5c and 6e).	DISCUSS
68	72	haem	chemical	In the current study, the Y113 residue plays a crucial role for the haem-dependent dimerization of PGRMC1 and resultant regulation of cancer proliferation and chemoresistance (Figs 5c and 6e).	DISCUSS
83	95	dimerization	oligomeric_state	In the current study, the Y113 residue plays a crucial role for the haem-dependent dimerization of PGRMC1 and resultant regulation of cancer proliferation and chemoresistance (Figs 5c and 6e).	DISCUSS
99	105	PGRMC1	protein	In the current study, the Y113 residue plays a crucial role for the haem-dependent dimerization of PGRMC1 and resultant regulation of cancer proliferation and chemoresistance (Figs 5c and 6e).	DISCUSS
10	14	Y113	residue_name_number	Since the Y113 residue is involved in the putative consensus motif of phosphorylation by tyrosine kinases such as Abl and Lck, we investigated whether phosphorylated Y113 is present in HCT116 cells by ESI-MS analysis.	DISCUSS
51	66	consensus motif	structure_element	Since the Y113 residue is involved in the putative consensus motif of phosphorylation by tyrosine kinases such as Abl and Lck, we investigated whether phosphorylated Y113 is present in HCT116 cells by ESI-MS analysis.	DISCUSS
70	85	phosphorylation	ptm	Since the Y113 residue is involved in the putative consensus motif of phosphorylation by tyrosine kinases such as Abl and Lck, we investigated whether phosphorylated Y113 is present in HCT116 cells by ESI-MS analysis.	DISCUSS
89	105	tyrosine kinases	protein_type	Since the Y113 residue is involved in the putative consensus motif of phosphorylation by tyrosine kinases such as Abl and Lck, we investigated whether phosphorylated Y113 is present in HCT116 cells by ESI-MS analysis.	DISCUSS
114	117	Abl	protein_type	Since the Y113 residue is involved in the putative consensus motif of phosphorylation by tyrosine kinases such as Abl and Lck, we investigated whether phosphorylated Y113 is present in HCT116 cells by ESI-MS analysis.	DISCUSS
122	125	Lck	protein_type	Since the Y113 residue is involved in the putative consensus motif of phosphorylation by tyrosine kinases such as Abl and Lck, we investigated whether phosphorylated Y113 is present in HCT116 cells by ESI-MS analysis.	DISCUSS
151	165	phosphorylated	protein_state	Since the Y113 residue is involved in the putative consensus motif of phosphorylation by tyrosine kinases such as Abl and Lck, we investigated whether phosphorylated Y113 is present in HCT116 cells by ESI-MS analysis.	DISCUSS
166	170	Y113	residue_name_number	Since the Y113 residue is involved in the putative consensus motif of phosphorylation by tyrosine kinases such as Abl and Lck, we investigated whether phosphorylated Y113 is present in HCT116 cells by ESI-MS analysis.	DISCUSS
201	207	ESI-MS	experimental_method	Since the Y113 residue is involved in the putative consensus motif of phosphorylation by tyrosine kinases such as Abl and Lck, we investigated whether phosphorylated Y113 is present in HCT116 cells by ESI-MS analysis.	DISCUSS
38	44	PGRMC1	protein	Recently, Peluso et al. reported that PGRMC1 binds to PGRMC2, suggesting that MAPR family members may also undergo haem-mediated heterodimerization.	DISCUSS
54	60	PGRMC2	protein	Recently, Peluso et al. reported that PGRMC1 binds to PGRMC2, suggesting that MAPR family members may also undergo haem-mediated heterodimerization.	DISCUSS
78	82	MAPR	protein_type	Recently, Peluso et al. reported that PGRMC1 binds to PGRMC2, suggesting that MAPR family members may also undergo haem-mediated heterodimerization.	DISCUSS
115	119	haem	chemical	Recently, Peluso et al. reported that PGRMC1 binds to PGRMC2, suggesting that MAPR family members may also undergo haem-mediated heterodimerization.	DISCUSS
19	23	haem	chemical	We showed that the haem-mediated dimer of PGRMC1 enables interaction with different subclasses of cytochromes P450 (CYP) (Fig. 6).	DISCUSS
33	38	dimer	oligomeric_state	We showed that the haem-mediated dimer of PGRMC1 enables interaction with different subclasses of cytochromes P450 (CYP) (Fig. 6).	DISCUSS
42	48	PGRMC1	protein	We showed that the haem-mediated dimer of PGRMC1 enables interaction with different subclasses of cytochromes P450 (CYP) (Fig. 6).	DISCUSS
98	114	cytochromes P450	protein_type	We showed that the haem-mediated dimer of PGRMC1 enables interaction with different subclasses of cytochromes P450 (CYP) (Fig. 6).	DISCUSS
116	119	CYP	protein_type	We showed that the haem-mediated dimer of PGRMC1 enables interaction with different subclasses of cytochromes P450 (CYP) (Fig. 6).	DISCUSS
21	27	PGRMC1	protein	While the effects of PGRMC1 on cholesterol synthesis mediated by CYP51 have been well documented in yeast and human cells, it has not been clear whether drug-metabolizing CYP activities are regulated by PGRMC1.	DISCUSS
65	70	CYP51	protein	While the effects of PGRMC1 on cholesterol synthesis mediated by CYP51 have been well documented in yeast and human cells, it has not been clear whether drug-metabolizing CYP activities are regulated by PGRMC1.	DISCUSS
100	105	yeast	taxonomy_domain	While the effects of PGRMC1 on cholesterol synthesis mediated by CYP51 have been well documented in yeast and human cells, it has not been clear whether drug-metabolizing CYP activities are regulated by PGRMC1.	DISCUSS
110	115	human	species	While the effects of PGRMC1 on cholesterol synthesis mediated by CYP51 have been well documented in yeast and human cells, it has not been clear whether drug-metabolizing CYP activities are regulated by PGRMC1.	DISCUSS
171	174	CYP	protein_type	While the effects of PGRMC1 on cholesterol synthesis mediated by CYP51 have been well documented in yeast and human cells, it has not been clear whether drug-metabolizing CYP activities are regulated by PGRMC1.	DISCUSS
203	209	PGRMC1	protein	While the effects of PGRMC1 on cholesterol synthesis mediated by CYP51 have been well documented in yeast and human cells, it has not been clear whether drug-metabolizing CYP activities are regulated by PGRMC1.	DISCUSS
42	48	PGRMC1	protein	Szczesna-Skorupa and Kemper reported that PGRMC1 exhibited an inhibitory effect on CYP3A4 drug metabolizing activity by competitively binding with cytochrome P450 reductase (CPR) in HEK293 or HepG2 cells.	DISCUSS
83	89	CYP3A4	protein	Szczesna-Skorupa and Kemper reported that PGRMC1 exhibited an inhibitory effect on CYP3A4 drug metabolizing activity by competitively binding with cytochrome P450 reductase (CPR) in HEK293 or HepG2 cells.	DISCUSS
147	172	cytochrome P450 reductase	protein	Szczesna-Skorupa and Kemper reported that PGRMC1 exhibited an inhibitory effect on CYP3A4 drug metabolizing activity by competitively binding with cytochrome P450 reductase (CPR) in HEK293 or HepG2 cells.	DISCUSS
174	177	CPR	protein	Szczesna-Skorupa and Kemper reported that PGRMC1 exhibited an inhibitory effect on CYP3A4 drug metabolizing activity by competitively binding with cytochrome P450 reductase (CPR) in HEK293 or HepG2 cells.	DISCUSS
44	50	PGRMC1	protein	On the other hand, Oda et al. reported that PGRMC1 had no effect to CYP2E1 and CYP3A4 activities in HepG2 cell.	DISCUSS
68	74	CYP2E1	protein	On the other hand, Oda et al. reported that PGRMC1 had no effect to CYP2E1 and CYP3A4 activities in HepG2 cell.	DISCUSS
79	85	CYP3A4	protein	On the other hand, Oda et al. reported that PGRMC1 had no effect to CYP2E1 and CYP3A4 activities in HepG2 cell.	DISCUSS
33	39	PGRMC1	protein	Several other groups showed that PGRMC1 enhanced chemoresistance in several cancer cells such as uterine sarcoma, breast cancer, endometrial tumour and ovarian cancer; however, no evidence of PGRMC1-dependent regulation of CYP activity was provided.	DISCUSS
192	198	PGRMC1	protein	Several other groups showed that PGRMC1 enhanced chemoresistance in several cancer cells such as uterine sarcoma, breast cancer, endometrial tumour and ovarian cancer; however, no evidence of PGRMC1-dependent regulation of CYP activity was provided.	DISCUSS
223	226	CYP	protein_type	Several other groups showed that PGRMC1 enhanced chemoresistance in several cancer cells such as uterine sarcoma, breast cancer, endometrial tumour and ovarian cancer; however, no evidence of PGRMC1-dependent regulation of CYP activity was provided.	DISCUSS
24	30	PGRMC1	protein	Our results showed that PGRMC1 contributes to enhancement of the doxorubicin metabolism, which is mediated by CYP2D6 or CYP3A4 in human colon cancer HCT116 cells (Fig. 6d).	DISCUSS
65	76	doxorubicin	chemical	Our results showed that PGRMC1 contributes to enhancement of the doxorubicin metabolism, which is mediated by CYP2D6 or CYP3A4 in human colon cancer HCT116 cells (Fig. 6d).	DISCUSS
110	116	CYP2D6	protein	Our results showed that PGRMC1 contributes to enhancement of the doxorubicin metabolism, which is mediated by CYP2D6 or CYP3A4 in human colon cancer HCT116 cells (Fig. 6d).	DISCUSS
120	126	CYP3A4	protein	Our results showed that PGRMC1 contributes to enhancement of the doxorubicin metabolism, which is mediated by CYP2D6 or CYP3A4 in human colon cancer HCT116 cells (Fig. 6d).	DISCUSS
130	135	human	species	Our results showed that PGRMC1 contributes to enhancement of the doxorubicin metabolism, which is mediated by CYP2D6 or CYP3A4 in human colon cancer HCT116 cells (Fig. 6d).	DISCUSS
45	48	CYP	protein_type	While the effects of structural diversity of CYP family proteins and interactions with different xenobiotic substrates should further be examined, the current results suggest that the interaction of drug-metabolizing CYPs with the haem-mediated dimer of PGRMC1 plays a crucial role in regulating their activities.	DISCUSS
217	221	CYPs	protein_type	While the effects of structural diversity of CYP family proteins and interactions with different xenobiotic substrates should further be examined, the current results suggest that the interaction of drug-metabolizing CYPs with the haem-mediated dimer of PGRMC1 plays a crucial role in regulating their activities.	DISCUSS
231	235	haem	chemical	While the effects of structural diversity of CYP family proteins and interactions with different xenobiotic substrates should further be examined, the current results suggest that the interaction of drug-metabolizing CYPs with the haem-mediated dimer of PGRMC1 plays a crucial role in regulating their activities.	DISCUSS
245	250	dimer	oligomeric_state	While the effects of structural diversity of CYP family proteins and interactions with different xenobiotic substrates should further be examined, the current results suggest that the interaction of drug-metabolizing CYPs with the haem-mediated dimer of PGRMC1 plays a crucial role in regulating their activities.	DISCUSS
254	260	PGRMC1	protein	While the effects of structural diversity of CYP family proteins and interactions with different xenobiotic substrates should further be examined, the current results suggest that the interaction of drug-metabolizing CYPs with the haem-mediated dimer of PGRMC1 plays a crucial role in regulating their activities.	DISCUSS
15	19	haem	chemical	We showed that haem-mediated dimerization of PGRMC1 enhances proliferation and chemoresistance of cancer cells through binding to and regulating EGFR and cytochromes P450 (illustrated in Fig. 7).	DISCUSS
29	41	dimerization	oligomeric_state	We showed that haem-mediated dimerization of PGRMC1 enhances proliferation and chemoresistance of cancer cells through binding to and regulating EGFR and cytochromes P450 (illustrated in Fig. 7).	DISCUSS
45	51	PGRMC1	protein	We showed that haem-mediated dimerization of PGRMC1 enhances proliferation and chemoresistance of cancer cells through binding to and regulating EGFR and cytochromes P450 (illustrated in Fig. 7).	DISCUSS
145	149	EGFR	protein_type	We showed that haem-mediated dimerization of PGRMC1 enhances proliferation and chemoresistance of cancer cells through binding to and regulating EGFR and cytochromes P450 (illustrated in Fig. 7).	DISCUSS
154	170	cytochromes P450	protein_type	We showed that haem-mediated dimerization of PGRMC1 enhances proliferation and chemoresistance of cancer cells through binding to and regulating EGFR and cytochromes P450 (illustrated in Fig. 7).	DISCUSS
10	31	haem-binding affinity	evidence	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
35	41	PGRMC1	protein	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
65	77	constitutive	protein_state	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
78	99	haem-binding proteins	protein_type	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
108	117	myoglobin	protein	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
119	125	PGMRC1	protein	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
161	164	apo	protein_state	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
165	172	monomer	oligomeric_state	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
177	187	haem-bound	protein_state	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
188	193	dimer	oligomeric_state	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
244	248	haem	chemical	Since the haem-binding affinity of PGRMC1 is lower than those of constitutive haem-binding proteins such as myoglobin, PGMRC1 is probably interconverted between apo-monomer and haem-bound dimer forms in response to changes in the intracellular haem concentration.	DISCUSS
67	71	haem	chemical	Considering microenvironments in and around malignant tumours, the haem concentration in cancer cells is likely to be elevated through multiple mechanisms, such as (i) an increased intake of haem, (ii) mutation of enzymes in TCA cycle (for example, fumarate hydratase) that increases the level of succinyl CoA, a substrate for haem biosynthesis and (iii) metastasis to haem-rich organs such as liver, brain and bone marrow.	DISCUSS
191	195	haem	chemical	Considering microenvironments in and around malignant tumours, the haem concentration in cancer cells is likely to be elevated through multiple mechanisms, such as (i) an increased intake of haem, (ii) mutation of enzymes in TCA cycle (for example, fumarate hydratase) that increases the level of succinyl CoA, a substrate for haem biosynthesis and (iii) metastasis to haem-rich organs such as liver, brain and bone marrow.	DISCUSS
249	267	fumarate hydratase	protein_type	Considering microenvironments in and around malignant tumours, the haem concentration in cancer cells is likely to be elevated through multiple mechanisms, such as (i) an increased intake of haem, (ii) mutation of enzymes in TCA cycle (for example, fumarate hydratase) that increases the level of succinyl CoA, a substrate for haem biosynthesis and (iii) metastasis to haem-rich organs such as liver, brain and bone marrow.	DISCUSS
297	309	succinyl CoA	chemical	Considering microenvironments in and around malignant tumours, the haem concentration in cancer cells is likely to be elevated through multiple mechanisms, such as (i) an increased intake of haem, (ii) mutation of enzymes in TCA cycle (for example, fumarate hydratase) that increases the level of succinyl CoA, a substrate for haem biosynthesis and (iii) metastasis to haem-rich organs such as liver, brain and bone marrow.	DISCUSS
327	331	haem	chemical	Considering microenvironments in and around malignant tumours, the haem concentration in cancer cells is likely to be elevated through multiple mechanisms, such as (i) an increased intake of haem, (ii) mutation of enzymes in TCA cycle (for example, fumarate hydratase) that increases the level of succinyl CoA, a substrate for haem biosynthesis and (iii) metastasis to haem-rich organs such as liver, brain and bone marrow.	DISCUSS
369	373	haem	chemical	Considering microenvironments in and around malignant tumours, the haem concentration in cancer cells is likely to be elevated through multiple mechanisms, such as (i) an increased intake of haem, (ii) mutation of enzymes in TCA cycle (for example, fumarate hydratase) that increases the level of succinyl CoA, a substrate for haem biosynthesis and (iii) metastasis to haem-rich organs such as liver, brain and bone marrow.	DISCUSS
220	224	haem	chemical	Moreover, exposure of cancer cells to stimuli such as hypoxia, radiation and chemotherapy causes cell damages and leads to protein degradation, resulting in increased levels of TCA cycle intermediates and in an enhanced haem biosynthesis.	DISCUSS
29	33	haem	chemical	On the other hand, excessive haem induces HO-1, the enzyme that oxidatively degrades haem and generates CO.	DISCUSS
42	46	HO-1	protein	On the other hand, excessive haem induces HO-1, the enzyme that oxidatively degrades haem and generates CO.	DISCUSS
85	89	haem	chemical	On the other hand, excessive haem induces HO-1, the enzyme that oxidatively degrades haem and generates CO.	DISCUSS
104	106	CO	chemical	On the other hand, excessive haem induces HO-1, the enzyme that oxidatively degrades haem and generates CO.	DISCUSS
6	10	HO-1	protein	Thus, HO-1 induction in cancer cells may inhibit the haem-mediated dimerization of PGRMC1 through the production of CO and thereby suppress tumour progression.	DISCUSS
53	57	haem	chemical	Thus, HO-1 induction in cancer cells may inhibit the haem-mediated dimerization of PGRMC1 through the production of CO and thereby suppress tumour progression.	DISCUSS
67	79	dimerization	oligomeric_state	Thus, HO-1 induction in cancer cells may inhibit the haem-mediated dimerization of PGRMC1 through the production of CO and thereby suppress tumour progression.	DISCUSS
83	89	PGRMC1	protein	Thus, HO-1 induction in cancer cells may inhibit the haem-mediated dimerization of PGRMC1 through the production of CO and thereby suppress tumour progression.	DISCUSS
116	118	CO	chemical	Thus, HO-1 induction in cancer cells may inhibit the haem-mediated dimerization of PGRMC1 through the production of CO and thereby suppress tumour progression.	DISCUSS
50	54	HO-1	protein	This idea is consistent with the observation that HO-1 induction or CO inhibits tumour growth.	DISCUSS
68	70	CO	chemical	This idea is consistent with the observation that HO-1 induction or CO inhibits tumour growth.	DISCUSS
32	38	PGRMC1	protein	Besides the regulatory roles of PGRMC1/Sigma-2 receptor in proliferation and chemoresistance in cancer cells (ref.), recent reports show that PGRMC1 is able to bind to amyloid beta oligomer to enhance its neurotoxicity.	DISCUSS
39	46	Sigma-2	protein	Besides the regulatory roles of PGRMC1/Sigma-2 receptor in proliferation and chemoresistance in cancer cells (ref.), recent reports show that PGRMC1 is able to bind to amyloid beta oligomer to enhance its neurotoxicity.	DISCUSS
142	148	PGRMC1	protein	Besides the regulatory roles of PGRMC1/Sigma-2 receptor in proliferation and chemoresistance in cancer cells (ref.), recent reports show that PGRMC1 is able to bind to amyloid beta oligomer to enhance its neurotoxicity.	DISCUSS
168	180	amyloid beta	protein	Besides the regulatory roles of PGRMC1/Sigma-2 receptor in proliferation and chemoresistance in cancer cells (ref.), recent reports show that PGRMC1 is able to bind to amyloid beta oligomer to enhance its neurotoxicity.	DISCUSS
181	189	oligomer	oligomeric_state	Besides the regulatory roles of PGRMC1/Sigma-2 receptor in proliferation and chemoresistance in cancer cells (ref.), recent reports show that PGRMC1 is able to bind to amyloid beta oligomer to enhance its neurotoxicity.	DISCUSS
13	20	Sigma-2	protein	Furthermore, Sigma-2 ligand-binding is decreased in transgenic amyloid beta deposition model APP/PS1 female mice.	DISCUSS
48	54	PGRMC1	protein	These results suggest a possible involvement of PGRMC1 in Alzheimer's disease.	DISCUSS
13	17	haem	chemical	The roles of haem-dependent dimerization of PGRMC1 in the functional regulation of its target proteins deserve further studies to find evidence that therapeutic interventions to interfere with the function of the dimer may control varied disease conditions.	DISCUSS
28	40	dimerization	oligomeric_state	The roles of haem-dependent dimerization of PGRMC1 in the functional regulation of its target proteins deserve further studies to find evidence that therapeutic interventions to interfere with the function of the dimer may control varied disease conditions.	DISCUSS
44	50	PGRMC1	protein	The roles of haem-dependent dimerization of PGRMC1 in the functional regulation of its target proteins deserve further studies to find evidence that therapeutic interventions to interfere with the function of the dimer may control varied disease conditions.	DISCUSS
213	218	dimer	oligomeric_state	The roles of haem-dependent dimerization of PGRMC1 in the functional regulation of its target proteins deserve further studies to find evidence that therapeutic interventions to interfere with the function of the dimer may control varied disease conditions.	DISCUSS
109	117	oligomer	oligomeric_state	Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity	REF
0	23	X-ray crystal structure	evidence	X-ray crystal structure of PGRMC1.	FIG
27	33	PGRMC1	protein	X-ray crystal structure of PGRMC1.	FIG
21	27	PGRMC1	protein	(a) Structure of the PGRMC1 dimer formed through stacked haems.	FIG
28	33	dimer	oligomeric_state	(a) Structure of the PGRMC1 dimer formed through stacked haems.	FIG
57	62	haems	chemical	(a) Structure of the PGRMC1 dimer formed through stacked haems.	FIG
4	10	PGRMC1	protein	Two PGRMC1 subunits (blue and green ribbons) dimerize via stacking of the haem molecules.	FIG
11	19	subunits	structure_element	Two PGRMC1 subunits (blue and green ribbons) dimerize via stacking of the haem molecules.	FIG
45	53	dimerize	oligomeric_state	Two PGRMC1 subunits (blue and green ribbons) dimerize via stacking of the haem molecules.	FIG
58	66	stacking	bond_interaction	Two PGRMC1 subunits (blue and green ribbons) dimerize via stacking of the haem molecules.	FIG
74	78	haem	chemical	Two PGRMC1 subunits (blue and green ribbons) dimerize via stacking of the haem molecules.	FIG
4	8	Haem	chemical	(b) Haem coordination of PGRMC1 with Tyr113.	FIG
9	21	coordination	bond_interaction	(b) Haem coordination of PGRMC1 with Tyr113.	FIG
25	31	PGRMC1	protein	(b) Haem coordination of PGRMC1 with Tyr113.	FIG
37	43	Tyr113	residue_name_number	(b) Haem coordination of PGRMC1 with Tyr113.	FIG
14	20	PGRMC1	protein	Comparison of PGRMC1 (blue) and cytochrome b5 (yellow, ID: 3NER). (c) PGRMC1 has a longer helix (a.a.147–163), which is shifted away from the haem (arrow).	FIG
32	45	cytochrome b5	protein_type	Comparison of PGRMC1 (blue) and cytochrome b5 (yellow, ID: 3NER). (c) PGRMC1 has a longer helix (a.a.147–163), which is shifted away from the haem (arrow).	FIG
70	76	PGRMC1	protein	Comparison of PGRMC1 (blue) and cytochrome b5 (yellow, ID: 3NER). (c) PGRMC1 has a longer helix (a.a.147–163), which is shifted away from the haem (arrow).	FIG
90	95	helix	structure_element	Comparison of PGRMC1 (blue) and cytochrome b5 (yellow, ID: 3NER). (c) PGRMC1 has a longer helix (a.a.147–163), which is shifted away from the haem (arrow).	FIG
101	108	147–163	residue_range	Comparison of PGRMC1 (blue) and cytochrome b5 (yellow, ID: 3NER). (c) PGRMC1 has a longer helix (a.a.147–163), which is shifted away from the haem (arrow).	FIG
142	146	haem	chemical	Comparison of PGRMC1 (blue) and cytochrome b5 (yellow, ID: 3NER). (c) PGRMC1 has a longer helix (a.a.147–163), which is shifted away from the haem (arrow).	FIG
0	6	PGRCM1	protein	PGRCM1 is dimerized by binding with haem.	FIG
10	19	dimerized	protein_state	PGRCM1 is dimerized by binding with haem.	FIG
36	40	haem	chemical	PGRCM1 is dimerized by binding with haem.	FIG
4	22	Mass spectrometric	experimental_method	(a) Mass spectrometric analyses of the wild-type (wt) PGRMC1 or the C129S mutant in the presence or absence of haem under non-denaturing condition.	FIG
39	48	wild-type	protein_state	(a) Mass spectrometric analyses of the wild-type (wt) PGRMC1 or the C129S mutant in the presence or absence of haem under non-denaturing condition.	FIG
50	52	wt	protein_state	(a) Mass spectrometric analyses of the wild-type (wt) PGRMC1 or the C129S mutant in the presence or absence of haem under non-denaturing condition.	FIG
54	60	PGRMC1	protein	(a) Mass spectrometric analyses of the wild-type (wt) PGRMC1 or the C129S mutant in the presence or absence of haem under non-denaturing condition.	FIG
68	73	C129S	mutant	(a) Mass spectrometric analyses of the wild-type (wt) PGRMC1 or the C129S mutant in the presence or absence of haem under non-denaturing condition.	FIG
74	80	mutant	protein_state	(a) Mass spectrometric analyses of the wild-type (wt) PGRMC1 or the C129S mutant in the presence or absence of haem under non-denaturing condition.	FIG
88	96	presence	protein_state	(a) Mass spectrometric analyses of the wild-type (wt) PGRMC1 or the C129S mutant in the presence or absence of haem under non-denaturing condition.	FIG
100	110	absence of	protein_state	(a) Mass spectrometric analyses of the wild-type (wt) PGRMC1 or the C129S mutant in the presence or absence of haem under non-denaturing condition.	FIG
111	115	haem	chemical	(a) Mass spectrometric analyses of the wild-type (wt) PGRMC1 or the C129S mutant in the presence or absence of haem under non-denaturing condition.	FIG
41	47	44–195	residue_range	Both proteins had identical lengths (a.a.44–195).	FIG
4	10	SV-AUC	experimental_method	(b) SV-AUC analyses of the wt-PGRMC1 and the C129S mutant (a.a.44–195) in the presence or absence of haem.	FIG
27	29	wt	protein_state	(b) SV-AUC analyses of the wt-PGRMC1 and the C129S mutant (a.a.44–195) in the presence or absence of haem.	FIG
30	36	PGRMC1	protein	(b) SV-AUC analyses of the wt-PGRMC1 and the C129S mutant (a.a.44–195) in the presence or absence of haem.	FIG
45	50	C129S	mutant	(b) SV-AUC analyses of the wt-PGRMC1 and the C129S mutant (a.a.44–195) in the presence or absence of haem.	FIG
51	57	mutant	protein_state	(b) SV-AUC analyses of the wt-PGRMC1 and the C129S mutant (a.a.44–195) in the presence or absence of haem.	FIG
63	69	44–195	residue_range	(b) SV-AUC analyses of the wt-PGRMC1 and the C129S mutant (a.a.44–195) in the presence or absence of haem.	FIG
78	86	presence	protein_state	(b) SV-AUC analyses of the wt-PGRMC1 and the C129S mutant (a.a.44–195) in the presence or absence of haem.	FIG
90	100	absence of	protein_state	(b) SV-AUC analyses of the wt-PGRMC1 and the C129S mutant (a.a.44–195) in the presence or absence of haem.	FIG
101	105	haem	chemical	(b) SV-AUC analyses of the wt-PGRMC1 and the C129S mutant (a.a.44–195) in the presence or absence of haem.	FIG
0	6	SV-AUC	experimental_method	SV-AUC experiments were performed with 1.5 mg ml−1 of PGRMC1 proteins.	FIG
54	60	PGRMC1	protein	SV-AUC experiments were performed with 1.5 mg ml−1 of PGRMC1 proteins.	FIG
20	45	sedimentation coefficient	evidence	The major peak with sedimentation coefficient S20,w of 1.9∼2.0 S (monomer) or 3.1 S (dimer) was detected.	FIG
46	51	S20,w	evidence	The major peak with sedimentation coefficient S20,w of 1.9∼2.0 S (monomer) or 3.1 S (dimer) was detected.	FIG
66	73	monomer	oligomeric_state	The major peak with sedimentation coefficient S20,w of 1.9∼2.0 S (monomer) or 3.1 S (dimer) was detected.	FIG
85	90	dimer	oligomeric_state	The major peak with sedimentation coefficient S20,w of 1.9∼2.0 S (monomer) or 3.1 S (dimer) was detected.	FIG
4	33	Difference absorption spectra	evidence	(c) Difference absorption spectra of PGRMC1 (a.a.44–195) titrated with haem (left panel).	FIG
37	43	PGRMC1	protein	(c) Difference absorption spectra of PGRMC1 (a.a.44–195) titrated with haem (left panel).	FIG
49	55	44–195	residue_range	(c) Difference absorption spectra of PGRMC1 (a.a.44–195) titrated with haem (left panel).	FIG
57	70	titrated with	experimental_method	(c) Difference absorption spectra of PGRMC1 (a.a.44–195) titrated with haem (left panel).	FIG
71	75	haem	chemical	(c) Difference absorption spectra of PGRMC1 (a.a.44–195) titrated with haem (left panel).	FIG
4	19	titration curve	evidence	The titration curve of haem to PGRMC1 (right panel).	FIG
23	27	haem	chemical	The titration curve of haem to PGRMC1 (right panel).	FIG
31	37	PGRMC1	protein	The titration curve of haem to PGRMC1 (right panel).	FIG
4	25	absorbance difference	evidence	The absorbance difference at 400 nm is plotted against the haem concentration.	FIG
59	63	haem	chemical	The absorbance difference at 400 nm is plotted against the haem concentration.	FIG
0	15	Carbon monoxide	chemical	Carbon monoxide inhibits haem-dependent PGRMC1 dimerization.	FIG
25	29	haem	chemical	Carbon monoxide inhibits haem-dependent PGRMC1 dimerization.	FIG
40	46	PGRMC1	protein	Carbon monoxide inhibits haem-dependent PGRMC1 dimerization.	FIG
47	59	dimerization	oligomeric_state	Carbon monoxide inhibits haem-dependent PGRMC1 dimerization.	FIG
4	33	UV-visible absorption spectra	evidence	(a) UV-visible absorption spectra of PGRMC1 (a.a.44–195).	FIG
37	43	PGRMC1	protein	(a) UV-visible absorption spectra of PGRMC1 (a.a.44–195).	FIG
49	55	44–195	residue_range	(a) UV-visible absorption spectra of PGRMC1 (a.a.44–195).	FIG
35	46	presence of	protein_state	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
51	59	oxidized	protein_state	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
68	72	haem	chemical	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
74	80	ferric	protein_state	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
87	94	reduced	protein_state	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
103	107	haem	chemical	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
109	116	ferrous	protein_state	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
126	133	reduced	protein_state	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
142	146	haem	chemical	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
152	154	CO	chemical	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
160	167	ferrous	protein_state	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
168	170	CO	chemical	Measurements were performed in the presence of the oxidized form of haem (ferric), the reduced form of haem (ferrous) and the reduced form of haem plus CO gas (ferrous+CO).	FIG
21	34	haem stacking	bond_interaction	(b) Close-up view of haem stacking.	FIG
4	33	Gel-filtration chromatography	experimental_method	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
46	52	PGRMC1	protein	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
58	64	44–195	residue_range	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
66	75	wild-type	protein_state	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
77	79	wt	protein_state	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
89	94	Y113F	mutant	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
98	103	C129S	mutant	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
104	110	mutant	protein_state	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
118	126	presence	protein_state	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
130	140	absence of	protein_state	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
141	145	haem	chemical	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
147	157	dithionite	chemical	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
165	167	CO	chemical	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
219	225	PGRMC1	protein	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
241	245	haem	chemical	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
250	252	CO	chemical	(c) Gel-filtration chromatography analyses of PGRMC1 (a.a.44–195) wild-type (wt) and the Y113F or C129S mutant in the presence or absence of haem, dithionite and/or CO. (d) Transition model for structural regulation of PGRMC1 in response to haem and CO.	FIG
0	4	Haem	chemical	Haem-dependent dimerization of PGRMC1 is necessary for tumour proliferation mediated by EGFR signalling.	FIG
15	27	dimerization	oligomeric_state	Haem-dependent dimerization of PGRMC1 is necessary for tumour proliferation mediated by EGFR signalling.	FIG
31	37	PGRMC1	protein	Haem-dependent dimerization of PGRMC1 is necessary for tumour proliferation mediated by EGFR signalling.	FIG
88	92	EGFR	protein_type	Haem-dependent dimerization of PGRMC1 is necessary for tumour proliferation mediated by EGFR signalling.	FIG
9	15	PGRMC1	protein	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
16	25	wild-type	protein_state	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
27	29	wt	protein_state	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
35	40	Y113F	mutant	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
41	47	mutant	protein_state	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
62	68	44–195	residue_range	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
81	84	apo	protein_state	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
89	99	haem-bound	protein_state	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
111	120	incubated	experimental_method	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
135	139	EGFR	protein_type	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
144	165	co-immunoprecipitated	experimental_method	(a) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo- or haem-bound form, were incubated with purified EGFR and co-immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
42	58	Western blotting	experimental_method	Input and bound proteins were detected by Western blotting.	FIG
42	58	Western blotting	experimental_method	Input and bound proteins were detected by Western blotting.	FIG
4	26	In vitro binding assay	experimental_method	(b) In vitro binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt (a.a.44–195) and purified EGFR with or without treatment of RuCl3 and CORM3.	FIG
57	67	haem-bound	protein_state	(b) In vitro binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt (a.a.44–195) and purified EGFR with or without treatment of RuCl3 and CORM3.	FIG
73	79	PGRMC1	protein	(b) In vitro binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt (a.a.44–195) and purified EGFR with or without treatment of RuCl3 and CORM3.	FIG
80	82	wt	protein_state	(b) In vitro binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt (a.a.44–195) and purified EGFR with or without treatment of RuCl3 and CORM3.	FIG
88	94	44–195	residue_range	(b) In vitro binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt (a.a.44–195) and purified EGFR with or without treatment of RuCl3 and CORM3.	FIG
109	113	EGFR	protein_type	(b) In vitro binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt (a.a.44–195) and purified EGFR with or without treatment of RuCl3 and CORM3.	FIG
143	148	RuCl3	chemical	(b) In vitro binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt (a.a.44–195) and purified EGFR with or without treatment of RuCl3 and CORM3.	FIG
153	158	CORM3	chemical	(b) In vitro binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt (a.a.44–195) and purified EGFR with or without treatment of RuCl3 and CORM3.	FIG
9	15	PGRMC1	protein	(c) FLAG-PGRMC1 wt or Y113F (full length) was over-expressed in HCT116 cells and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
16	18	wt	protein_state	(c) FLAG-PGRMC1 wt or Y113F (full length) was over-expressed in HCT116 cells and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
22	27	Y113F	mutant	(c) FLAG-PGRMC1 wt or Y113F (full length) was over-expressed in HCT116 cells and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
29	40	full length	protein_state	(c) FLAG-PGRMC1 wt or Y113F (full length) was over-expressed in HCT116 cells and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
46	60	over-expressed	experimental_method	(c) FLAG-PGRMC1 wt or Y113F (full length) was over-expressed in HCT116 cells and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
81	99	immunoprecipitated	experimental_method	(c) FLAG-PGRMC1 wt or Y113F (full length) was over-expressed in HCT116 cells and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
0	21	Co-immunoprecipitated	experimental_method	Co-immunoprecipitated proteins (FLAG-PGRMC1, endogenous PGRMC1 and EGFR) were detected with Western blotting by using anti-PGRMC1 or anti-EGFR antibody.	FIG
37	43	PGRMC1	protein	Co-immunoprecipitated proteins (FLAG-PGRMC1, endogenous PGRMC1 and EGFR) were detected with Western blotting by using anti-PGRMC1 or anti-EGFR antibody.	FIG
45	55	endogenous	protein_state	Co-immunoprecipitated proteins (FLAG-PGRMC1, endogenous PGRMC1 and EGFR) were detected with Western blotting by using anti-PGRMC1 or anti-EGFR antibody.	FIG
56	62	PGRMC1	protein	Co-immunoprecipitated proteins (FLAG-PGRMC1, endogenous PGRMC1 and EGFR) were detected with Western blotting by using anti-PGRMC1 or anti-EGFR antibody.	FIG
67	71	EGFR	protein_type	Co-immunoprecipitated proteins (FLAG-PGRMC1, endogenous PGRMC1 and EGFR) were detected with Western blotting by using anti-PGRMC1 or anti-EGFR antibody.	FIG
92	108	Western blotting	experimental_method	Co-immunoprecipitated proteins (FLAG-PGRMC1, endogenous PGRMC1 and EGFR) were detected with Western blotting by using anti-PGRMC1 or anti-EGFR antibody.	FIG
123	129	PGRMC1	protein	Co-immunoprecipitated proteins (FLAG-PGRMC1, endogenous PGRMC1 and EGFR) were detected with Western blotting by using anti-PGRMC1 or anti-EGFR antibody.	FIG
138	142	EGFR	protein_type	Co-immunoprecipitated proteins (FLAG-PGRMC1, endogenous PGRMC1 and EGFR) were detected with Western blotting by using anti-PGRMC1 or anti-EGFR antibody.	FIG
62	77	succinylacetone	chemical	(d) HCT116 cells were treated with or without 250 μmol l−1 of succinylacetone (SA) for 48 h. The intracellular haem was extracted and quantified by reverse-phase HPLC.	FIG
79	81	SA	chemical	(d) HCT116 cells were treated with or without 250 μmol l−1 of succinylacetone (SA) for 48 h. The intracellular haem was extracted and quantified by reverse-phase HPLC.	FIG
111	115	haem	chemical	(d) HCT116 cells were treated with or without 250 μmol l−1 of succinylacetone (SA) for 48 h. The intracellular haem was extracted and quantified by reverse-phase HPLC.	FIG
148	166	reverse-phase HPLC	experimental_method	(d) HCT116 cells were treated with or without 250 μmol l−1 of succinylacetone (SA) for 48 h. The intracellular haem was extracted and quantified by reverse-phase HPLC.	FIG
54	70	Student's t-test	experimental_method	of four separate experiments. **P<0.01 using unpaired Student's t-test. (e) Co-immunoprecipitation assay was performed as in (c) with or without SA treatment in HCT116 cells.	FIG
76	104	Co-immunoprecipitation assay	experimental_method	of four separate experiments. **P<0.01 using unpaired Student's t-test. (e) Co-immunoprecipitation assay was performed as in (c) with or without SA treatment in HCT116 cells.	FIG
145	147	SA	chemical	of four separate experiments. **P<0.01 using unpaired Student's t-test. (e) Co-immunoprecipitation assay was performed as in (c) with or without SA treatment in HCT116 cells.	FIG
36	41	shRNA	chemical	(f) HCT116 cells expressing control shRNA or those knocking down PGRMC1 (PGRMC1-KD) were treated with EGF or left untreated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
51	64	knocking down	experimental_method	(f) HCT116 cells expressing control shRNA or those knocking down PGRMC1 (PGRMC1-KD) were treated with EGF or left untreated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
65	71	PGRMC1	protein	(f) HCT116 cells expressing control shRNA or those knocking down PGRMC1 (PGRMC1-KD) were treated with EGF or left untreated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
73	82	PGRMC1-KD	mutant	(f) HCT116 cells expressing control shRNA or those knocking down PGRMC1 (PGRMC1-KD) were treated with EGF or left untreated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
102	105	EGF	protein_type	(f) HCT116 cells expressing control shRNA or those knocking down PGRMC1 (PGRMC1-KD) were treated with EGF or left untreated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
147	151	EGFR	protein_type	(f) HCT116 cells expressing control shRNA or those knocking down PGRMC1 (PGRMC1-KD) were treated with EGF or left untreated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
187	203	Western blotting	experimental_method	(f) HCT116 cells expressing control shRNA or those knocking down PGRMC1 (PGRMC1-KD) were treated with EGF or left untreated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
48	51	EGF	protein_type	(g,h) HCT116 cells were treated with or without EGF, SA, RuCl3 and CORM3 as indicated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
53	55	SA	chemical	(g,h) HCT116 cells were treated with or without EGF, SA, RuCl3 and CORM3 as indicated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
57	62	RuCl3	chemical	(g,h) HCT116 cells were treated with or without EGF, SA, RuCl3 and CORM3 as indicated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
67	72	CORM3	chemical	(g,h) HCT116 cells were treated with or without EGF, SA, RuCl3 and CORM3 as indicated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
109	113	EGFR	protein_type	(g,h) HCT116 cells were treated with or without EGF, SA, RuCl3 and CORM3 as indicated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
149	165	Western blotting	experimental_method	(g,h) HCT116 cells were treated with or without EGF, SA, RuCl3 and CORM3 as indicated, and components of the EGFR signaling pathway were detected by Western blotting.	FIG
0	4	Haem	chemical	Haem-dependent dimerization of PGRMC1 accelerates tumour growth through the EGFR signaling pathway.	FIG
15	27	dimerization	oligomeric_state	Haem-dependent dimerization of PGRMC1 accelerates tumour growth through the EGFR signaling pathway.	FIG
31	37	PGRMC1	protein	Haem-dependent dimerization of PGRMC1 accelerates tumour growth through the EGFR signaling pathway.	FIG
76	80	EGFR	protein_type	Haem-dependent dimerization of PGRMC1 accelerates tumour growth through the EGFR signaling pathway.	FIG
28	34	PGRMC1	protein	(a) Nucleotide sequences of PGRMC1 targeted by shRNA and of the shRNA-resistant full length PGRMC1 expression vector.	FIG
47	52	shRNA	chemical	(a) Nucleotide sequences of PGRMC1 targeted by shRNA and of the shRNA-resistant full length PGRMC1 expression vector.	FIG
64	79	shRNA-resistant	protein_state	(a) Nucleotide sequences of PGRMC1 targeted by shRNA and of the shRNA-resistant full length PGRMC1 expression vector.	FIG
80	91	full length	protein_state	(a) Nucleotide sequences of PGRMC1 targeted by shRNA and of the shRNA-resistant full length PGRMC1 expression vector.	FIG
92	98	PGRMC1	protein	(a) Nucleotide sequences of PGRMC1 targeted by shRNA and of the shRNA-resistant full length PGRMC1 expression vector.	FIG
7	23	PGRMC1-knockdown	mutant	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
25	34	PGRMC1-KD	mutant	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
54	77	transiently transfected	experimental_method	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
87	102	shRNA-resistant	protein_state	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
103	120	expression vector	experimental_method	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
124	133	wild-type	protein_state	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
134	140	PGRMC1	protein	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
142	144	wt	protein_state	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
153	158	Y113F	mutant	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
159	165	mutant	protein_state	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
167	172	Y113F	mutant	Stable PGRMC1-knockdown (PGRMC1-KD) HCT116 cells were transiently transfected with the shRNA-resistant expression vector of wild-type PGRMC1 (wt) or the Y113F mutant (Y113F).	FIG
4	13	Erlotinib	chemical	(b) Erlotinib was added to HCT116 (control) cells, PGRMC1-KD cells or PGRMC1-KD cells expressing shRNA-resistant PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
51	60	PGRMC1-KD	mutant	(b) Erlotinib was added to HCT116 (control) cells, PGRMC1-KD cells or PGRMC1-KD cells expressing shRNA-resistant PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
70	79	PGRMC1-KD	mutant	(b) Erlotinib was added to HCT116 (control) cells, PGRMC1-KD cells or PGRMC1-KD cells expressing shRNA-resistant PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
97	112	shRNA-resistant	protein_state	(b) Erlotinib was added to HCT116 (control) cells, PGRMC1-KD cells or PGRMC1-KD cells expressing shRNA-resistant PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
113	119	PGRMC1	protein	(b) Erlotinib was added to HCT116 (control) cells, PGRMC1-KD cells or PGRMC1-KD cells expressing shRNA-resistant PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
120	122	wt	protein_state	(b) Erlotinib was added to HCT116 (control) cells, PGRMC1-KD cells or PGRMC1-KD cells expressing shRNA-resistant PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
126	131	Y113F	mutant	(b) Erlotinib was added to HCT116 (control) cells, PGRMC1-KD cells or PGRMC1-KD cells expressing shRNA-resistant PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
168	177	MTT assay	experimental_method	(b) Erlotinib was added to HCT116 (control) cells, PGRMC1-KD cells or PGRMC1-KD cells expressing shRNA-resistant PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
30	32	*P	evidence	of four separate experiments. *P<0.01 using ANOVA with Fischer's LSD test.	FIG
44	49	ANOVA	experimental_method	of four separate experiments. *P<0.01 using ANOVA with Fischer's LSD test.	FIG
55	73	Fischer's LSD test	experimental_method	of four separate experiments. *P<0.01 using ANOVA with Fischer's LSD test.	FIG
30	32	*P	evidence	of four separate experiments. *P<0.01 using ANOVA with Fischer's LSD test.	FIG
44	49	ANOVA	experimental_method	of four separate experiments. *P<0.01 using ANOVA with Fischer's LSD test.	FIG
55	73	Fischer's LSD test	experimental_method	of four separate experiments. *P<0.01 using ANOVA with Fischer's LSD test.	FIG
38	47	PGRMC1-KD	mutant	(c) Spheroid formation in control and PGRMC1-KD HCT116 cells.	FIG
54	56	*P	evidence	The graph represents mean±s.e. of each spheroid size. *P<0.01 using ANOVA with Fischer's LSD test.	FIG
68	73	ANOVA	experimental_method	The graph represents mean±s.e. of each spheroid size. *P<0.01 using ANOVA with Fischer's LSD test.	FIG
79	97	Fischer's LSD test	experimental_method	The graph represents mean±s.e. of each spheroid size. *P<0.01 using ANOVA with Fischer's LSD test.	FIG
74	96	intrasplenic injection	experimental_method	Scale bar: 0.1 mm. (d) Tumour-bearing livers of NOG mice at 10 days after intrasplenic injection of HCT116 (control) or PGRMC1-KD cells.	FIG
120	129	PGRMC1-KD	mutant	Scale bar: 0.1 mm. (d) Tumour-bearing livers of NOG mice at 10 days after intrasplenic injection of HCT116 (control) or PGRMC1-KD cells.	FIG
28	30	*P	evidence	of 10 separate experiments. *P<0.05 using unpaired Student's t-test.	FIG
51	67	Student's t-test	experimental_method	of 10 separate experiments. *P<0.05 using unpaired Student's t-test.	FIG
0	4	Haem	chemical	Haem-dependent PGRMC1 dimerization enhances tumour chemoresistance through interaction with cytochromes P450.	FIG
15	21	PGRMC1	protein	Haem-dependent PGRMC1 dimerization enhances tumour chemoresistance through interaction with cytochromes P450.	FIG
22	34	dimerization	oligomeric_state	Haem-dependent PGRMC1 dimerization enhances tumour chemoresistance through interaction with cytochromes P450.	FIG
92	108	cytochromes P450	protein_type	Haem-dependent PGRMC1 dimerization enhances tumour chemoresistance through interaction with cytochromes P450.	FIG
11	17	PGRMC1	protein	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
18	27	wild-type	protein_state	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
29	31	wt	protein_state	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
37	42	Y113F	mutant	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
43	49	mutant	protein_state	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
64	70	44–195	residue_range	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
83	86	apo	protein_state	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
90	100	haem-bound	protein_state	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
112	121	incubated	experimental_method	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
127	133	CYP1A2	protein	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
141	147	CYP3A4	protein	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
156	174	immunoprecipitated	experimental_method	(a,b) FLAG-PGRMC1 wild-type (wt) and Y113F mutant proteins (a.a.44–195), in either apo or haem-bound form, were incubated with CYP1A2 (a) or CYP3A4 (b) and immunoprecipitated with anti-FLAG antibody-conjugated beads.	FIG
4	17	Binding assay	experimental_method	(c) Binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt and CYP1A2 with or without RuCl3 and CORM3.	FIG
48	58	haem-bound	protein_state	(c) Binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt and CYP1A2 with or without RuCl3 and CORM3.	FIG
64	70	PGRMC1	protein	(c) Binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt and CYP1A2 with or without RuCl3 and CORM3.	FIG
71	73	wt	protein_state	(c) Binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt and CYP1A2 with or without RuCl3 and CORM3.	FIG
78	84	CYP1A2	protein	(c) Binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt and CYP1A2 with or without RuCl3 and CORM3.	FIG
101	106	RuCl3	chemical	(c) Binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt and CYP1A2 with or without RuCl3 and CORM3.	FIG
111	116	CORM3	chemical	(c) Binding assay was performed as in (a) using haem-bound FLAG-PGRMC1 wt and CYP1A2 with or without RuCl3 and CORM3.	FIG
30	41	doxorubicin	chemical	(d) Schematic illustration of doxorubicin metabolism is shown on the left.	FIG
0	11	Doxorubicin	chemical	Doxorubicin was incubated with HCT116 cells expressing control shRNA or shPGRMC1 (PGRMC1-KD), and the doxorubicinol/doxorubicin ratios in cell pellets were determined using LC-MS.	FIG
16	25	incubated	experimental_method	Doxorubicin was incubated with HCT116 cells expressing control shRNA or shPGRMC1 (PGRMC1-KD), and the doxorubicinol/doxorubicin ratios in cell pellets were determined using LC-MS.	FIG
63	68	shRNA	chemical	Doxorubicin was incubated with HCT116 cells expressing control shRNA or shPGRMC1 (PGRMC1-KD), and the doxorubicinol/doxorubicin ratios in cell pellets were determined using LC-MS.	FIG
72	80	shPGRMC1	chemical	Doxorubicin was incubated with HCT116 cells expressing control shRNA or shPGRMC1 (PGRMC1-KD), and the doxorubicinol/doxorubicin ratios in cell pellets were determined using LC-MS.	FIG
82	91	PGRMC1-KD	mutant	Doxorubicin was incubated with HCT116 cells expressing control shRNA or shPGRMC1 (PGRMC1-KD), and the doxorubicinol/doxorubicin ratios in cell pellets were determined using LC-MS.	FIG
102	115	doxorubicinol	chemical	Doxorubicin was incubated with HCT116 cells expressing control shRNA or shPGRMC1 (PGRMC1-KD), and the doxorubicinol/doxorubicin ratios in cell pellets were determined using LC-MS.	FIG
116	127	doxorubicin	chemical	Doxorubicin was incubated with HCT116 cells expressing control shRNA or shPGRMC1 (PGRMC1-KD), and the doxorubicinol/doxorubicin ratios in cell pellets were determined using LC-MS.	FIG
173	178	LC-MS	experimental_method	Doxorubicin was incubated with HCT116 cells expressing control shRNA or shPGRMC1 (PGRMC1-KD), and the doxorubicinol/doxorubicin ratios in cell pellets were determined using LC-MS.	FIG
31	33	*P	evidence	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
69	85	Student's t-test	experimental_method	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
112	123	doxorubicin	chemical	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
162	171	PGRMC1-KD	mutant	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
182	191	PGRMC1-KD	mutant	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
209	224	shRNA-resistant	protein_state	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
225	236	full-length	protein_state	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
237	243	PGRMC1	protein	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
244	246	wt	protein_state	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
250	255	Y113F	mutant	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
292	301	MTT assay	experimental_method	of four separate experiments. **P<0.01 versus control using unpaired Student's t-test. (e) Indicated amounts of doxorubicin were added to HCT116 (control) cells, PGRMC1-KD cells, or PGRMC1-KD cells expressing shRNA-resistant full-length PGRMC1 wt or Y113F, and cell viability was examined by MTT assay.	FIG
40	46	PGRMC1	protein	Schematic diagram for the regulation of PGRMC1 functions.	FIG
0	3	Apo	protein_state	Apo-PGRMC1 exists as an inactive monomer.	FIG
4	10	PGRMC1	protein	Apo-PGRMC1 exists as an inactive monomer.	FIG
24	32	inactive	protein_state	Apo-PGRMC1 exists as an inactive monomer.	FIG
33	40	monomer	oligomeric_state	Apo-PGRMC1 exists as an inactive monomer.	FIG
3	13	binding to	protein_state	On binding to haem, PGRMC1 forms a dimer through stacking interactions between the haem moieties, which enables PGRMC1 to interact with EGFR and cytochromes P450, leading to an enhanced proliferation and chemoresistance of cancer cells.	FIG
14	18	haem	chemical	On binding to haem, PGRMC1 forms a dimer through stacking interactions between the haem moieties, which enables PGRMC1 to interact with EGFR and cytochromes P450, leading to an enhanced proliferation and chemoresistance of cancer cells.	FIG
20	26	PGRMC1	protein	On binding to haem, PGRMC1 forms a dimer through stacking interactions between the haem moieties, which enables PGRMC1 to interact with EGFR and cytochromes P450, leading to an enhanced proliferation and chemoresistance of cancer cells.	FIG
35	40	dimer	oligomeric_state	On binding to haem, PGRMC1 forms a dimer through stacking interactions between the haem moieties, which enables PGRMC1 to interact with EGFR and cytochromes P450, leading to an enhanced proliferation and chemoresistance of cancer cells.	FIG
49	70	stacking interactions	bond_interaction	On binding to haem, PGRMC1 forms a dimer through stacking interactions between the haem moieties, which enables PGRMC1 to interact with EGFR and cytochromes P450, leading to an enhanced proliferation and chemoresistance of cancer cells.	FIG
83	87	haem	chemical	On binding to haem, PGRMC1 forms a dimer through stacking interactions between the haem moieties, which enables PGRMC1 to interact with EGFR and cytochromes P450, leading to an enhanced proliferation and chemoresistance of cancer cells.	FIG
112	118	PGRMC1	protein	On binding to haem, PGRMC1 forms a dimer through stacking interactions between the haem moieties, which enables PGRMC1 to interact with EGFR and cytochromes P450, leading to an enhanced proliferation and chemoresistance of cancer cells.	FIG
136	140	EGFR	protein_type	On binding to haem, PGRMC1 forms a dimer through stacking interactions between the haem moieties, which enables PGRMC1 to interact with EGFR and cytochromes P450, leading to an enhanced proliferation and chemoresistance of cancer cells.	FIG
145	161	cytochromes P450	protein_type	On binding to haem, PGRMC1 forms a dimer through stacking interactions between the haem moieties, which enables PGRMC1 to interact with EGFR and cytochromes P450, leading to an enhanced proliferation and chemoresistance of cancer cells.	FIG
0	2	CO	chemical	CO interferes with the stacking interactions of the haems and thereby inhibits PGRMC1 functions.	FIG
23	44	stacking interactions	bond_interaction	CO interferes with the stacking interactions of the haems and thereby inhibits PGRMC1 functions.	FIG
52	57	haems	chemical	CO interferes with the stacking interactions of the haems and thereby inhibits PGRMC1 functions.	FIG
79	85	PGRMC1	protein	CO interferes with the stacking interactions of the haems and thereby inhibits PGRMC1 functions.	FIG
39	51	dimerization	oligomeric_state	PGRMC1 proteins exhibit haem-dependent dimerization in solution.	TABLE
360	365	C129S	mutant	" 	Apo form	Haem-bound form	 	 	 	Mass (Da)	 	Mass (Da)	 	aPGRMC1 wt (a.a.44–195)	 	 ESI-MS	—	17,844.14	—	36,920.19	 	 Theoretical	 	17,843.65	 	36,918.06	 	 	Hydrodynamic radius 10−9 (m)	MW (kDa)	Hydrodynamic radius 10−9 (m)	MW (kDa)	 	 DOSY	2.04–2.15	20	2.94–3.02	42	 	 	S20,w (S)	MW (kDa)	S20,w (S)	MW (kDa)	 	 SV-AUC	1.9	17.6	3.1	35.5	 	 	 	 	 	 	 	bPGRMC1 C129S (a.a.44–195)	 	 ESI-MS	—	17,827.91	—	36,887.07	 	 Theoretical	 	17,827.59	 	36,885.6	 	 	S20,w (S)	MW (kDa)	S20,w (S)	MW (kDa)	 	 SV-AUC	2.0	18.1	3.1	35.8	 	"	TABLE
66	71	C129S	mutant	Differences in molecular weights of the wild-type (wt; a) and the C129S mutant (b) PGRMC1 proteins in the absence (apo form) or the presence of haem (haem-bound form).	TABLE
32	37	C129S	mutant	The protein sizes of the wt and C129S PGRMC1 cytosolic domains (a.a.44–195) in the presence or absence of haem were estimated by ESI-MS, DOSY and SV-AUC.	TABLE