SII-SWORD/CoKE huggingface dataset:
ADAP, PH domain 2 (PH2_ADAP)
Type: Domain

ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate . Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity .

This entry contains the second PH domain repeat.
Net1, PH domain (Net1_PH)
Type: Domain

Net1 (also called ArhGEF8) is a RhoA-specific GEF (guanine nucleotide exchange factors). Net1 binds to caspase activation and recruitment domain (CARD)- and membrane-associated guanylate kinase-like domain-containing (CARMA) proteins and regulates nuclear factor kB activation . In nucleus, it also regulates RhoB-mediated cell death after DNA damage . Net1 and RhoA have been shown to play important roles in various aspects of vertebrate embryonic development and organogenesis .

Net1 contains a catalytic Dbl homology (DH) domain and an adjacent pleckstrin homology (PH) domain flanked by N- and C-terminal extensions . This entry represents the PH domain. The DH and PH domains are necessary for binding to the GTPase and stimulating nucleotide exchange activity .
Vacuolar protein sorting protein 36 (Vps36)
Type: Family

Vps36 is a subunit of ESCRT-II, a protein complex involved in driving protein sorting from endosomes to lysosomes. The GLUE domain of Vps36 allows for a tight interaction to occur between the protein and Vps28, a subunit of ESCRT-I. This interaction is critical for ubiquitinated cargo progression from early to late endosomes .

The multivesicular body (MVB) protein-sorting pathway targets transmembrane proteins either for degradation or for function in the vacuole/lysosomes. The signal for entry into this pathway is monoubiquitination of protein cargo, which results in incorporation of cargo into luminal vesicles at late endosomes. Another crucial player is phosphatidylinositol 3-phosphate (PtdINS(3)P), which is enriched on early endosomes and on the luminal vesicles of MVBs. ESCRT (endosomal sorting complex required for transport)-I, -II and -III complexes are critical for MVB budding and sorting of monoubiquitinated cargo into the luminal vesicles . Various Ub-binding domains (UBDs), such as UIM, UEV and NZF are found in such machineries .

The Vps 36 subunit of the ESCRT-II trafficking complex binds both phosphoinositides and ubiquitin. All members of the Vps36 family contain a divergent GRAM/PH-like domain; yeast and some other fungi have one or two NZF domains inserted in the GRAM/PH-like domain .
Sdc1/DPY30 (Sdc1/DPY30)
Type: Family

This entry includes Sdc1 from fission yeast, and its homologues, Dpy-30, from animals.

Protein dpy-30 homologue (DPY30) is a component of the MLL1/MLL complex which trimethylates histone H3 at 'Lys-4' as a specific tag for epigenetic transcriptional activation . DPY30 is also a component in MLL2/3 and MLL4/WBP7 methyltransferase-containing complexes and the SET1 complex . DPY30 is found in the nucleus and the trans-Golgi network where it interacts with ARFGEF1 implying a role in endosomal trafficking . This entry also includes C. elegans dpy-30, which is an essential component of the C. elegans dosage compensation machinery that reduces X chromosome transcript levels in hermaphrodites (XX) .

The SET1 complex is a methyltransferase that that produces trimethylated histone H3 at Lys(4). It is composed of at least the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1, HCFC1 and DPY30 . In yeast there is only one SET1 complex, but in mammals there are additional H3K4 methylases .
MTMR1, PH-GRAM (MTMR1_PH-GRAM)
Type: Domain

MTMR1 (myotubularin-related protein 1) is a lipid phosphatase that uses phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] as substrates . MTMR1 is abnormally expressed in myotonic dystrophy type1 (DM1) and in myotonic dystrophy type 2 (DM2), in correlation with muscle pathological features .

The myotubularin family constitutes a large group of conserved proteins, with 14 members in humans consisting of myotubularin (MTM1) and 13 myotubularin-related proteins (MTMR1-MTMR13). Orthologues have been found throughout the eukaryotic kingdom, but not in bacteria. MTM1 dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) to phosphatidylinositol and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] to phosphatidylinositol 5-monophosphate (PI5P) [

,

, . The substrate phosphoinositides (PIs) are known to regulate traffic within the endosomal-lysosomal pathway . MTMR1, MTMR2, MTMR3, MTMR4, and MTMR6 have also been shown to utilise PI(3)P as a substrate, suggesting that this activity is intrinsic to all active family members. On the other hand, six of the MTM family members encode for catalytically inactive phosphatases. Inactive myotubularin phosphatases contain substitutions in the Cys and Arg residues of the Cys-X5-Arg motif. MTM pseudophosphatases have been found to interact with MTM catalytic phosphatases . The myotubularin family includes several members mutated in neuromuscular diseases or associated with metabolic syndrome, obesity, and cancer .

Most MTMRs contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, a PTP domain (which may be active or inactive), a SET-interaction domain, and a C-terminal coiled-coil region. In addition some members contain DENN domain N-terminal to the PH-GRAM domain and FYVE, PDZ, and PH domains C-terminal to the coiled-coil region . The GRAM domain, found in myotubularins, glucosyltransferases, and other putative membrane-associated proteins, is part of a larger motif with a pleckstrin homology (PH) domain fold .
ARAP, RhoGAP domain (RhoGAP_ARAP)
Type: Domain

This entry represenst a RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in ARAPs. ARAPs (also known as centaurin deltas) are dual GTPase activating proteins (GAPs) for Arf and Rho family GTPases, and contain, besides the Rho-GAP domain, an Arf-GAP, ankyrin repeat ras-associating, and PH domains. Since their Arf-GAP activity is PIP3-dependent, ARAPs are considered integration points for phosphoinositide, Arf and Rho signaling .

Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude .
Chimaerin, RhoGAP domain (RhoGAP_chimaerin)
Type: Domain

This entry represents the RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of chimaerins.

Chimaerin is a family of GTPase activating proteins for the small G-protein Rac. Chimaerin family members have been implicated in development, neuritogenesis and cancer .
PLC-beta, PH domain (PLC-beta_PH)
Type: Domain

PLC-beta (PLCbeta) is regulated by heterotrimeric G protein-coupled receptors through their C2 domain and long C-terminal extension which forms an autoinhibitory helix. There are four isoforms: PLC-beta1-4. These isoforms mediate the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) to propagate signals for several physiological responses .

PLC-beta consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves, a C2 domain and a C-terminal PDZ. This entry represents the PH domain of PLC-beta. The PH domain of PLC-beta2 and PLC-beta3 plays a dual role, much like PLC-delta1, by binding to the plasma membrane, as well as the interaction site for the catalytic activator .
Rho GTPase-activating protein 6/36 (RHOGAP6/36)
Type: Family

Rho GTPase activating protein 6 (ArhGAP6/RHOGAP6) shows GAP activity towards RhoA, but not towards Cdc42 and Rac1 . ArhGAP6 is often deleted in microphthalmia with linear skin defects syndrome (MLS); MLS is a severe X-linked developmental disorder .

This family also includes ARHGAP36, which is a potent antagonist of PKA signalling .
Active breakpoint cluster region-related protein, PH domain (ABR_PH)
Type: Domain

The active breakpoint cluster region-related protein (ABR) protein contains multiple domains including a RhoGEF domain, a PH domain, a C1 domain, a C2 domain, and a C-terminal RhoGAP domain. It is related to a slightly larger protein, BCR, which is structurally similar, but has an additional N-terminal kinase domain. ABR has GAP activity for both Rac and Cdc42. It promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them .
COMPASS component Swd2/WDR82 (Swd2/WDR82)
Type: Family

This entry includes Swd2 from yeasts and WDR82 from animals. They are part of the Set1/COMPASS complex .

Besides being part of the Set1/COMPASS complex, Swd2 is also a component of the cleavage and polyadenylation factor (CPF) complex and its subcomplex APT .

The COMPASS (Complex Proteins Associated with Set1 or Set1C) is the yeast homologue of the human MLL complex, which is required for mono-, di-, and trimethylation of lysine 4 of histone H3 . It is required in telomeric transcriptional silencing . The complex consists of Set1, Bre2, Spp1, Sdc1, Shg1, Swd1, Swd2, and Swd3 .
Vacuolar protein sorting-associated protein 5, PX domain (PX_Vps5)
Type: Domain

The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system . The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway .

Vsp5 is the yeast counterpart of human SNX1 and is part of the retromer complex, which functions in the endosome-to-Golgi retrieval of vacuolar protein sorting receptor Vps10, the Golgi-resident membrane protein A-ALP, and endopeptidase Kex2. The PX domain of Vps5 binds phosphatidylinositol-3-phosphate (PI3P). Similar to SNX1, Vps5 contains a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. Both domains have been shown to determine the specific membrane-targeting of SNX1 .
Spp1/CFP1 (Spp1/CFP1)
Type: Family

Spp1 is a component of the COMPASS (Set1C) complex . It promotes meiotic DNA double-strand break formation in promoters by tethering histone H3K4 methylation sites to chromosome axes . This entry also includes CXXC-type zinc finger protein 1 (also known as CFP1) from animals .

CXXC-type zinc finger protein 1 (CXXC1 or CFP1) is a component of the SETD1 histone H3K4 methyltransferase complex. CXXC1 directs the complex to a chromatin region via its CXXC zinc finger with a specificity for a CpG unmethylated motif, particularly CpGG .

The COMPASS (Complex Proteins Associated with Set1 or Set1C) is the yeast homologue of the human MLL complex, which is required for mono-, di-, and trimethylation of lysine 4 of histone H3 . It is required in telomeric transcriptional silencing . The complex consists of Set1, Bre2, Spp1, Sdc1, Shg1, Swd1, Swd2, and Swd3 .
Phafin, PH domain (PH_Phafin)
Type: Domain

Phafin1 (also known as PLEKHF1 or LAPF) recruits phosphorylated p53 to lysosomes and triggers caspase-independent apoptosis. It is also is involved in lysosomal sorting and induction of autophagosome formation via Rab7 signaling . Phafin2 (also called EAPF, FLJ13187, ZFYVE18 or PLEKHF2) is differentially expressed in the liver cancer cell and regulates the structure and function of the endosomes through Rab5-dependent processes . Phafin2 modulates the cell's response to extracellular stimulation by modulating the receptor density on the cell surface .

Phafin1 and Phafin2 are composed of both PH and FYVE domains. Phafin1 has an additional C-terminal tail domain. Phafin1, but not phafin2, exhibits significant binding to PI(4)P and PI(5)P . This entry represents the PH domain of phafin 1 and 2.
Rab3 (Rab3)
Type: Family

The Rab3 subfamily contains Rab3A, Rab3B, Rab3C, and Rab3D. All four isoforms were found in mouse brain and endocrine tissues, with varying levels of expression. Rab3A, Rab3B, and Rab3C localized to synaptic and secretory vesicles; Rab3D was expressed at high levels only in adipose tissue, exocrine glands, and the endocrine pituitary, where it is localized to cytoplasmic secretory granules . Rab3 appears to control Ca2+-regulated exocytosis. The appropriate GDP/GTP exchange cycle of Rab3A is required for Ca2+-regulated exocytosis to occur, and interaction of the GTP-bound form of Rab3A with effector molecule(s) is widely believed to be essential for this process .
BamE-like (BamE-like)
Type: Homologous_superfamily

The fold of this superfamily, tandemly repeated in beta-lactamase-inhibitor BLIP, has an α(2)-β(4) structure . It is also found in osmotically-inducible lipoprotein OsmE, which has no known function , and in outer membrane protein assembly factor BamE.

BamE is part of the outer membrane protein (OMP) assembly Bam complex (composed of the outer membrane protein BamA, and four lipoproteins BamB, BamC, BamD and BamE), which is involved in assembly and insertion of β-barrel proteins into the outer membrane . E. coli BamE is a nonessential member of the complex that stabilizes the interaction between the essential proteins BamA and BamD. It may modulate the conformation of BamA, likely through interactions with BamD .
Cdc42 (Cdc42)
Type: Family

Cdc42 is an essential GTPase that belongs to the Rho family of Ras-like GTPases. These proteins act as molecular switches by responding to exogenous and/or endogenous signals and relaying those signals to activate downstream components of a biological pathway. Cdc42 transduces signals to the actin cytoskeleton to initiate and maintain polarized growth and to mitogen-activated protein morphogenesis. In Saccharomyces cerevisiae, Cdc42 plays an important role in multiple actin-dependent morphogenetic events such as bud emergence, mating-projection formation, and pseudohyphal growth . In mammalian cells, Cdc42 regulates a variety of actin-dependent events and induces the JNK/SAPK protein kinase cascade, which leads to the activation of transcription factors within the nucleus . Cdc42 mediates these processes through interactions with a myriad of downstream effectors, whose number and regulation we are just starting to understand. In addition, Cdc42 has been implicated in a number of human diseases through interactions with its regulators and downstream effectors .
Ribosome biogenesis protein Bms1, N-terminal (Bms1_N)
Type: Domain

Bms1 is an essential, evolutionarily conserved, nucleolar protein. Its depletion interferes with processing of the 35S pre-rRNA at sites A0, A1, and A2, and the formation of 40S subunits. Bms1, the putative endonuclease Rc11, and the essential U3 small nucleolar RNA form a stable subcomplex that is believed to control an early step in the formation of the 40S subunit . The N terminus of Bms1 contains a guanine nucleotide-binding (G) domain that functions intramolecularly. It is believed that Rc11 activates Bms1 by acting as a guanine-nucleotide exchange factor (GEF) to promote GDP/GTP exchange, and that activated (GTP-bound) Bms1 delivers Rc11 to the preribosomes .

This entry represents the N-terminal domain of Bms1.
Heat shock protein beta-1, ACD domain (ACD_HspB1)
Type: Domain

This entry represents the alpha crystallin domain (ACD) found in mammalian Hsp27 (also denoted HspB1 in human).

Small heat shock proteins (sHsps) are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits . They are characterised by the presence of an alpha crystallin domain (ACD) .

Hsp27 shows enhanced synthesis in response to stress. It is a molecular chaperone which interacts with a large number of different proteins. It is found in many types of human cells including breast, uterus, cervix, platelets and cancer cells. Hsp27 has diverse cellular functions including chaperoning, regulation of actin polymerization, keratinocyte differentiation, regulation of inflammatory pathways in keratinocytes, and protection from oxidative stress through modulating glutathione levels . It is also a subunit of AUF1-containing protein complexes . Hsp27 has been linked to several transduction pathways regulating cellular functions including differentiation, cell growth, development, and apoptosis . Its activity can be regulated by phosphorylation. Its unphosphorylated state is a high molecular weight aggregated form (100-800kDa) composed of up to 24 subunits, which forms as a result of multiple interactions within the ACD, and is required for chaperone function and resistance to oxidative stress. Upon phosphorylation these large aggregates rapidly disassociate to smaller oligomers and chaperone activity is modified .

High constitutive levels of Hsp27 have been detected in various cancer cells, in particular those of carcinoma origin . Over-expression of Hsp27 has a protective effect against various diseases-processes, including Huntington's disease . Mutations in Hsp27 have been associated with a form of distal hereditary motor neuropathy type II and Charcot-Marie-Tooth disease type 2 .
HMT2C, PHD3 (PHD3_KMT2C)
Type: Domain

Histone-lysine N-methyltransferases 2C (KMT2C, also known as MLL3 or homologous to ALR protein) methylates 'Lys-4' of histone H3 (H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation). It is a component of the MLL2/3 complex, which is essential for p53 transactivation of small heterodimer partner (SHP) . KMT2C functions as a circadian factor contributing to genome-scale circadian transcription . KMT2C is also a part of activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) that contains the transcriptional coactivator nuclear receptor coactivator 6 (NCOA6), KMT2C and its paralog MLL4. The ASCOM complex is critical for nuclear receptor (NR) activation of bile acid transporter genes and is down regulated in cholestasis .

KMT2C contains several plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, a high mobility group (HMG)-1 box, a SET
domain and two FY (phenylalanine tyrosine)-rich domains.

This entry represents the third PHD finger of KMT2C proteins.
Sperm acrosome membrane-associated protein 1 (SPACA1)
Type: Family

SPACA1 (also known as SAMP32) is localized to the acrosome of spermatozoa. The acrosome is an organelle transformed from the Golgi apparatus to form a cap over the anterior portion of the spermatozoa head, which contains the sperm nucleus. Mammalian acrosomes contain digestive enzymes that degrade the ovum outer membrane (zona pellucida) to allow fusion of the sperm and ovum nuclei via the acrosomal reaction . In mammals, the acrosome releases hyaluronidase and acrosin. Antibodies against recombinant SAMP32 inhibits both the binding and the fusion of human sperm to zona-free hamster eggs . Male mice lacking SPACA1 are infertile, and exhibit globozoospermia-like misformed sperm heads . SPACA1 content has been reported to be diminished in a comparison of round-headed and normal spermatozoa .
RGS10, RGS domain (RGS10_RGS)
Type: Domain

RGS (Regulator of G-protein Signaling) domain is an essential part of the RGS10 protein. RGS10 is a member of the RGS proteins family, a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). RGS10 is one of the smallest proteins of the RGS family; its structure is little more than the RGS domain. As a major G-protein regulator, RGS domain containing proteins are involved in many crucial cellular processes such as regulation of intracellular trafficking, glial differentiation, embryonic axis formation, skeletal and muscle development, and cell migration during early embryogenesis .
RGS12, RGS domain (RGS12_RGS)
Type: Domain

RGS (Regulator of G-protein Signaling) domain is an essential part of the RGS12 protein. RGS12 is a member of the RA/RGS subfamily of RGS proteins family, a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). As a major G-protein regulator, RGS domain containing proteins are involved in many crucial cellular processes such as regulation of intracellular trafficking, glial differentiation, embryonic axis formation, skeletal and muscle development, and cell migration during early embryogenesis .
RGS14, RGS domain (RGS14_RGS)
Type: Domain

RGS14 is a regulator of G protein signaling (RGS) protein and contains an N-terminal RGS domain, two tandem Ras-binding domains (RBDs) and a G protein regulatory (GPR, also referred to as a GoLoco) motif. It regulates G protein nucleotide exchange and hydrolysis by acting as a GTPase-activating protein (GAP) through its RGS domain, and as a guanine nucleotide dissociation inhibitor (GDI) through its GoLoco motif . Both domains of RGS14 target members of the Gialpha subclass . It is a microtubule-associated protein that may modulate microtubule dynamics and spindle formation and play an essential role during mammalian cell division . RGS14 regulates the activation of alphaMbeta2 integrin during phagocytosis . It is a key regulator of signalling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory .

This entry represents the RGS domain of RGS14.
Alpha-crystallin B chain, ACD domain (ACD_alphaB-crystallin)
Type: Domain

This entry represents the alpha-crystallin domain (ACD) found in the small heat shock protein (sHsp) alphaB-crystallin (HspB5, 20kDa).

sHsps are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits . They are characterised by the presence of an alpha-crystallin domain .

Alpha crystallin, an abundant protein in the mammalian lens, is a large (700kDa) heteropolymer composed of HspB4 and HspB5, generally in a molar ratio of HspB4:HspB5 of 3:1. HspB5 shows increased synthesis in response to stress. HspB5 is also expressed constitutively in other tissues including brain, heart, and type I and type IIa skeletal muscle fibres, and in several cancers including gliomas, renal cell carcinomas, basal-like and metaplastic breast carcinomas, and head and neck cancer. Its functions include effects on the apoptotic pathway and on metastasis. Phosphorylation of HspB5 reduces its oligomerization and anti-apoptotic activities. HspB5 is protective in demyelinating disease such as multiple sclerosis (MS), being a negative regulator of inflammation . In early active MS lesions it is the most abundant gene transcript and an autoantigen, the immune response against it would disrupt its function and worsen inflammation and demyelination. Given as therapy for ongoing demyelinating disease it may counteract this effect . It is an autoantigen in the pathogenesis of various other inflammatory disorders including Lens-associated uveitis (LAU), and Behcet's disease . Mutations in HspB5 have been associated with diseases including dominant cataract and desmin-related myopathy .