Protein: Guanine nucleotide exchange factor C9orf72 (Q96LT7)
Organism: Homo sapiens (Human)
Function: Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy. In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation. The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ULK1/ATG1 kinase complex and modulating its protein kinase activity. As part of the C9orf72-SMCR8 complex, stimulates RAB8A and RAB11A GTPase activity in vitro. Positively regulates initiation of autophagy by regulating the RAB1A-dependent trafficking of the ULK1/ATG1 kinase complex to the phagophore which leads to autophagosome formation. Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates. Plays a role in endosomal trafficking. May be involved in regulating the maturation of phagosomes to lysosomes (By similarity). Promotes the lysosomal localization and lysosome-mediated degradation of CARM1 which leads to inhibition of starvation-induced lipid metabolism (By similarity). Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation. This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to CFL1/cofilin activation. Positively regulates axon extension and axon growth cone size in spinal motor neurons. Required for SMCR8 protein expression and localization at pre- and post-synaptic compartments in the forebrain, also regulates protein abundance of RAB3A and GRIA1/GLUR1 in post-synaptic compartments in the forebrain and hippocampus (By similarity). Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity (By similarity).
Subcellular location: Nucleus {ECO:0000269|PubMed:21944779, ECO:0000269|PubMed:27037575}. Cytoplasm {ECO:0000269|PubMed:21944778, ECO:0000269|PubMed:27037575, ECO:0000269|PubMed:27193190}. Cytoplasm, P-body {ECO:0000269|PubMed:27037575}. Cytoplasm, Stress granule {ECO:0000269|PubMed:27037575}. Endosome {ECO:0000269|PubMed:24549040}. Lysosome {ECO:0000269|PubMed:24549040, ECO:0000269|PubMed:27559131}. Cytoplasmic vesicle, autophagosome {ECO:0000269|PubMed:24549040}. Secreted {ECO:0000269|PubMed:24549040}. Cell projection, axon {ECO:0000269|PubMed:27723745}. Cell projection, growth cone {ECO:0000269|PubMed:27723745}. Perikaryon {ECO:0000250|UniProtKB:Q6DFW0}. Note=Detected in the cytoplasm of neurons from brain tissue (PubMed:21944778). Detected in the nucleus in fibroblasts (PubMed:21944779). During corticogenesis, transitions from being predominantly cytoplasmic to a more even nucleocytoplasmic distribution (By similarity). {ECO:0000250|UniProtKB:Q6DFW0, ECO:0000269|PubMed:21944778, ECO:0000269|PubMed:21944779, ECO:0000269|PubMed:27037575}.; SUBCELLULAR LOCATION: [Isoform 1]: Perikaryon {ECO:0000269|PubMed:26174152}. Cell projection, dendrite {ECO:0000269|PubMed:26174152}. Presynapse {ECO:0000250|UniProtKB:Q6DFW0}. Postsynapse {ECO:0000250|UniProtKB:Q6DFW0}. Note=Expressed diffusely throughout the cytoplasm and dendritic processes of cerebellar Purkinje cells. Also expressed diffusely throughout the cytoplasm of spinal motor neurons. {ECO:0000269|PubMed:26174152}.; SUBCELLULAR LOCATION: [Isoform 2]: Nucleus membrane {ECO:0000269|PubMed:26174152}; Peripheral membrane protein {ECO:0000305}. Nucleus {ECO:0000269|PubMed:26174152}. Note=Detected at the nuclear membrane of cerebellar Purkinje cells and spinal motor neurons. Also shows diffuse nuclear expression in spinal motor neurons. {ECO:0000269|PubMed:26174152}.
Interaction partners:
- WD repeat-containing protein 41
- Guanine nucleotide exchange protein SMCR8
- Serine/threonine-protein kinase ULK1
- Ras-related protein Rab-1A
- RB1-inducible coiled-coil protein 1
- Ras-related protein Rab-39B
- Ras-related protein Rab-8A
- Autophagy-related protein 101
- TAR DNA-binding protein 43
- RNA-binding protein FUS
Sequence:
MSTLCPPPSPAVAKTEIALSGKSPLLAATFAYWDNILGPRVRHIWAPKTEQVLLSDGEITFLANHTLNGEILRNAESGAIDVKFFVLSEKGVIIVSLIFDGNWNGDRSTYGLSIILPQTELSFYLPLHRVCVDRLTHIIRKGRIWMHKERQENVQKIILEGTERMEDQGQSIIPMLTGEVIPVMELLSSMKSHSVPEEIDIADTVLNDDDIGDSCHEGFLLNAISSHLQTCGCSVVVGSSAEKVNKIVRTLCLFLTPAERKCSRLCEAESSFKYESGLFVQGLLKDSTGSFVLPFRQVMYAPYPTTHIDVDVNTVKQMPPCHEHIYNQRRYMRSELTAFWRATSEEDMAQDTIIYTDESFTPDLNIFQDVLHRDTLVKAFLDQVFQLKPGLSLRSTFLAQFLLVLHRKALTLIKYIEDDTQKGKKPFKSLRNLKIDLDLTAEGDLNIIMALAEKIKPGLHSFIFGRPFYTSVQERDVLMTF