UniProtKB - Q96LT7 (CI072_HUMAN)
Guanine nucleotide exchange factor C9orf72
C9orf72
Functioni
Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:27193190, PubMed:27103069, PubMed:27617292, PubMed:28195531, PubMed:32303654).
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 (PubMed:27103069).
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 (PubMed:27617292).
As part of the C9orf72-SMCR8 complex, stimulates RAB8A and RAB11A GTPase activity in vitro (PubMed:32303654).
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 (PubMed:27334615).
Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131).
Plays a role in endosomal trafficking (PubMed:24549040).
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 (PubMed:27723745).
This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to CFL1/cofilin activation (PubMed:27723745).
Positively regulates axon extension and axon growth cone size in spinal motor neurons (PubMed:27723745).
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).
By similarity9 PublicationsRegulates stress granule assembly in response to cellular stress.
1 PublicationDoes not play a role in regulation of stress granule assembly in response to cellular stress.
1 PublicationGO - Molecular functioni
- guanyl-nucleotide exchange factor activity Source: UniProtKB-KW
- small GTPase binding Source: UniProtKB
GO - Biological processi
- autophagy Source: UniProtKB
- axon extension Source: UniProtKB
- endocytosis Source: UniProtKB
- late endosome to lysosome transport Source: UniProtKB
- negative regulation of exocytosis Source: ComplexPortal
- negative regulation of GTP binding Source: Ensembl
- negative regulation of immune response Source: ComplexPortal
- negative regulation of protein phosphorylation Source: UniProtKB
- positive regulation of GTPase activity Source: UniProtKB
- positive regulation of macroautophagy Source: UniProtKB
- regulation of actin filament organization Source: UniProtKB
- regulation of autophagosome assembly Source: UniProtKB
- regulation of autophagy Source: UniProtKB
- regulation of protein localization Source: Ensembl
- regulation of TORC1 signaling Source: UniProtKB
- stress granule assembly Source: UniProtKB
Keywordsi
Molecular function | Guanine-nucleotide releasing factor |
Biological process | Autophagy |
Enzyme and pathway databases
PathwayCommonsi | Q96LT7 |
SignaLinki | Q96LT7 |
SIGNORi | Q96LT7 |
Names & Taxonomyi
Protein namesi | Recommended name: Guanine nucleotide exchange factor C9orf72Curated |
Gene namesi | |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:28337, C9orf72 |
MIMi | 614260, gene |
neXtProti | NX_Q96LT7 |
VEuPathDBi | HostDB:ENSG00000147894 |
Subcellular locationi
Extracellular region or secreted
- Secreted 1 Publication
Endosome
- Endosome 1 Publication
Lysosome
- Lysosome 2 Publications
Nucleus
- Nucleus 2 Publications
Cytoplasm and Cytosol
- Cytoplasm 3 Publications
Other locations
- P-body 1 Publication
- Stress granule 1 Publication
- autophagosome 1 Publication
- axon 1 Publication
- growth cone 1 Publication
- Perikaryon By similarity
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).By similarity3 Publications
Other locations
- Perikaryon 1 Publication
- dendrite 1 Publication
- presynapse By similarity
- postsynapse By similarity
Note: Expressed diffusely throughout the cytoplasm and dendritic processes of cerebellar Purkinje cells. Also expressed diffusely throughout the cytoplasm of spinal motor neurons.1 Publication
Nucleus
- Nucleus membrane 1 Publication; Peripheral membrane protein Curated
- Nucleus 1 Publication
Note: Detected at the nuclear membrane of cerebellar Purkinje cells and spinal motor neurons. Also shows diffuse nuclear expression in spinal motor neurons.1 Publication
Cytosol
- cytosol Source: HPA
Endosome
- endosome Source: UniProtKB
Extracellular region or secreted
- extracellular space Source: UniProtKB
Lysosome
- lysosome Source: UniProtKB
Nucleus
- nuclear membrane Source: UniProtKB
- nucleus Source: UniProtKB
Other locations
- autophagosome Source: UniProtKB
- axonal growth cone Source: UniProtKB
- cytoplasm Source: UniProtKB
- cytoplasmic stress granule Source: UniProtKB
- dendrite Source: UniProtKB
- Flemming body Source: HPA
- guanyl-nucleotide exchange factor complex Source: HGNC
- intracellular membrane-bounded organelle Source: HPA
- main axon Source: UniProtKB
- P-body Source: UniProtKB
- perikaryon Source: UniProtKB
- postsynapse Source: Ensembl
- presynapse Source: Ensembl
Keywords - Cellular componenti
Cell junction, Cell projection, Cytoplasm, Cytoplasmic vesicle, Endosome, Lysosome, Membrane, Nucleus, Secreted, SynapsePathology & Biotechi
Involvement in diseasei
Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1)4 Publications
Keywords - Diseasei
Amyotrophic lateral sclerosis, NeurodegenerationOrganism-specific databases
DisGeNETi | 203228 |
GeneReviewsi | C9orf72 |
MalaCardsi | C9orf72 |
MIMi | 105550, phenotype |
OpenTargetsi | ENSG00000147894 |
Orphaneti | 803, Amyotrophic lateral sclerosis 275864, Behavioral variant of frontotemporal dementia 275872, Frontotemporal dementia with motor neuron disease 401901, Huntington disease-like syndrome due to C9ORF72 expansions 100070, Progressive non-fluent aphasia 100069, Semantic dementia |
PharmGKBi | PA134908144 |
Miscellaneous databases
Pharosi | Q96LT7, Tbio |
Genetic variation databases
BioMutai | C9orf72 |
DMDMi | 71152412 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000089711 | 1 – 481 | Guanine nucleotide exchange factor C9orf72Add BLAST | 481 |
Proteomic databases
EPDi | Q96LT7 |
jPOSTi | Q96LT7 |
MassIVEi | Q96LT7 |
MaxQBi | Q96LT7 |
PaxDbi | Q96LT7 |
PeptideAtlasi | Q96LT7 |
PRIDEi | Q96LT7 |
ProteomicsDBi | 77248 [Q96LT7-1] 77249 [Q96LT7-2] |
PTM databases
iPTMneti | Q96LT7 |
PhosphoSitePlusi | Q96LT7 |
Expressioni
Tissue specificityi
Gene expression databases
Bgeei | ENSG00000147894, Expressed in monocyte and 210 other tissues |
ExpressionAtlasi | Q96LT7, baseline and differential |
Genevisiblei | Q96LT7, HS |
Organism-specific databases
HPAi | ENSG00000147894, Low tissue specificity |
Interactioni
Subunit structurei
Component of the C9orf72-SMCR8 complex, at least composed of C9orf72, SMCR8 and WDR41 (PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531, PubMed:32303654). The complex is formed of two protomers, each individually consisting of one molecule each of C9orf72, SMCR8 and WDR41 (PubMed:32303654). The protomers homodimerize via an interaction between C9orf72 (via C-terminus) and SMCR8 (via N-terminus) (PubMed:32303654). Within each protomer SMCR8 (via DENN domain) acts as a bridging protein between WDR41 (via C-terminus and N-terminus) and C9orf72 (via C-terminus) (PubMed:32303654). The C9orf72-SMCR8 complex associates with the ULK1/ATG1 kinase complex (PubMed:27617292, PubMed:28195531).
Interacts with ULK1/ATG1 kinase complex members ULK1, ATG13 and RB1CC1 (PubMed:27334615).
Interacts with SMCR8; the interaction is direct (PubMed:27559131, PubMed:27617292, PubMed:32303654).
Interacts with HNRNPA1, HNRNPA2B1 and UBQLN2 (PubMed:24549040).
Interacts with small Rab GTPase RAB1A; the interaction mediates recruitment of RAB1A to the ULK1/ATG1 kinase complex (PubMed:27334615).
Also interacts with small Rab GTPase RAB7A (By similarity).
Interacts with cofilin (PubMed:27723745).
Interacts with GTP-binding proteins ARF1 and ARF6 (By similarity).
Interacts with the DLG4/PSD-95 (By similarity).
Interacts with CARM1 (via PH domain-like fold) (By similarity).
By similarity9 PublicationsBinary interactionsi
Q96LT7
Isoform 1 [Q96LT7-1]
Isoform 2 [Q96LT7-2]
With | #Exp. | IntAct |
---|---|---|
ATG13 [O75143] | 4 | EBI-16693673,EBI-2798775 |
RAB1A [P62820] | 4 | EBI-16693673,EBI-716845 |
RB1CC1 [Q8TDY2] | 6 | EBI-16693673,EBI-1047793 |
ULK1 [O75385] | 4 | EBI-16693673,EBI-908831 |
GO - Molecular functioni
- small GTPase binding Source: UniProtKB
Protein-protein interaction databases
BioGRIDi | 128456, 120 interactors |
ComplexPortali | CPX-3961, C9orf72-SMCR8 complex [Q96LT7-1] |
CORUMi | Q96LT7 |
IntActi | Q96LT7, 108 interactors |
MINTi | Q96LT7 |
STRINGi | 9606.ENSP00000482753 |
Miscellaneous databases
RNActi | Q96LT7, protein |
Structurei
Secondary structure
3D structure databases
AlphaFoldDBi | Q96LT7 |
SMRi | Q96LT7 |
ModBasei | Search... |
PDBe-KBi | Search... |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 23 – 194 | uDENN C9ORF72-typePROSITE-ProRule annotationAdd BLAST | 172 | |
Domaini | 200 – 343 | cDENN C9ORF72-typePROSITE-ProRule annotationAdd BLAST | 144 | |
Domaini | 370 – 464 | dDENN C9ORF72-typePROSITE-ProRule annotationAdd BLAST | 95 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 461 – 481 | Required for the homodimerization of the C9orf72-SMCR8 complex1 PublicationAdd BLAST | 21 |
Phylogenomic databases
eggNOGi | ENOG502QSST, Eukaryota |
GeneTreei | ENSGT00390000005644 |
HOGENOMi | CLU_047573_0_0_1 |
InParanoidi | Q96LT7 |
OMAi | IFGRSFY |
OrthoDBi | 1434762at2759 |
PhylomeDBi | Q96LT7 |
TreeFami | TF313315 |
Family and domain databases
InterProi | View protein in InterPro IPR027819, C9orf72 |
PANTHERi | PTHR31855, PTHR31855, 1 hit |
Pfami | View protein in Pfam PF15019, C9orf72-like, 1 hit |
PROSITEi | View protein in PROSITE PS51835, DENN_C9ORF72, 1 hit |
s (2+)i Sequence
Sequence statusi: Complete.
This entry describes 2 produced by isoformsialternative splicing. AlignAdd to basketThis entry has 2 described isoforms and 3 potential isoforms that are computationally mapped.Show allAlign All
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MSTLCPPPSP AVAKTEIALS GKSPLLAATF AYWDNILGPR VRHIWAPKTE
60 70 80 90 100
QVLLSDGEIT FLANHTLNGE ILRNAESGAI DVKFFVLSEK GVIIVSLIFD
110 120 130 140 150
GNWNGDRSTY GLSIILPQTE LSFYLPLHRV CVDRLTHIIR KGRIWMHKER
160 170 180 190 200
QENVQKIILE GTERMEDQGQ SIIPMLTGEV IPVMELLSSM KSHSVPEEID
210 220 230 240 250
IADTVLNDDD IGDSCHEGFL LNAISSHLQT CGCSVVVGSS AEKVNKIVRT
260 270 280 290 300
LCLFLTPAER KCSRLCEAES SFKYESGLFV QGLLKDSTGS FVLPFRQVMY
310 320 330 340 350
APYPTTHIDV DVNTVKQMPP CHEHIYNQRR YMRSELTAFW RATSEEDMAQ
360 370 380 390 400
DTIIYTDESF TPDLNIFQDV LHRDTLVKAF LDQVFQLKPG LSLRSTFLAQ
410 420 430 440 450
FLLVLHRKAL TLIKYIEDDT QKGKKPFKSL RNLKIDLDLT AEGDLNIIMA
460 470 480
LAEKIKPGLH SFIFGRPFYT SVQERDVLMT F
Computationally mapped potential isoform sequencesi
There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketA0A2R8Y5K2 | A0A2R8Y5K2_HUMAN | Guanine nucleotide exchange factor ... | C9orf72 | 492 | Annotation score: | ||
A0A2R8Y5U5 | A0A2R8Y5U5_HUMAN | Guanine nucleotide exchange factor ... | C9orf72 | 373 | Annotation score: | ||
A0A5F9ZHW7 | A0A5F9ZHW7_HUMAN | Guanine nucleotide exchange factor ... | C9orf72 | 431 | Annotation score: |
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_050827 | 207 | N → S. Corresponds to variant dbSNP:rs17769294EnsemblClinVar. | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_014745 | 222 | N → K in isoform 2. 1 Publication | 1 | |
Alternative sequenceiVSP_014746 | 223 – 481 | Missing in isoform 2. 1 PublicationAdd BLAST | 259 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | JN681271 mRNA Translation: AET41697.1 AK057806 mRNA Translation: BAB71583.1 AK291425 mRNA Translation: BAF84114.1 AL451123 Genomic DNA No translation available. CH471071 Genomic DNA Translation: EAW58561.1 CH471071 Genomic DNA Translation: EAW58558.1 CH471071 Genomic DNA Translation: EAW58560.1 BC068445 mRNA Translation: AAH68445.1 |
CCDSi | CCDS6522.1 [Q96LT7-1] CCDS6523.1 [Q96LT7-2] |
RefSeqi | NP_001242983.1, NM_001256054.2 [Q96LT7-1] NP_060795.1, NM_018325.4 [Q96LT7-1] NP_659442.2, NM_145005.6 [Q96LT7-2] |
Genome annotation databases
Ensembli | ENST00000379995.1; ENSP00000369331.1; ENSG00000147894.17 [Q96LT7-2] ENST00000379997.7; ENSP00000369333.3; ENSG00000147894.17 [Q96LT7-2] ENST00000380003.8; ENSP00000369339.3; ENSG00000147894.17 ENST00000619707.5; ENSP00000482753.1; ENSG00000147894.17 |
GeneIDi | 203228 |
KEGGi | hsa:203228 |
MANE-Selecti | ENST00000380003.8; ENSP00000369339.3; NM_018325.5; NP_060795.1 |
UCSCi | uc003zqq.4, human [Q96LT7-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | JN681271 mRNA Translation: AET41697.1 AK057806 mRNA Translation: BAB71583.1 AK291425 mRNA Translation: BAF84114.1 AL451123 Genomic DNA No translation available. CH471071 Genomic DNA Translation: EAW58561.1 CH471071 Genomic DNA Translation: EAW58558.1 CH471071 Genomic DNA Translation: EAW58560.1 BC068445 mRNA Translation: AAH68445.1 |
CCDSi | CCDS6522.1 [Q96LT7-1] CCDS6523.1 [Q96LT7-2] |
RefSeqi | NP_001242983.1, NM_001256054.2 [Q96LT7-1] NP_060795.1, NM_018325.4 [Q96LT7-1] NP_659442.2, NM_145005.6 [Q96LT7-2] |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
6LT0 | electron microscopy | 3.20 | C/F | 1-481 | [»] | |
6V4U | electron microscopy | 3.80 | A | 1-481 | [»] | |
7MGE | electron microscopy | 3.94 | C | 1-481 | [»] | |
7O2W | electron microscopy | - | A | 1-481 | [»] | |
AlphaFoldDBi | Q96LT7 | |||||
SMRi | Q96LT7 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 128456, 120 interactors |
ComplexPortali | CPX-3961, C9orf72-SMCR8 complex [Q96LT7-1] |
CORUMi | Q96LT7 |
IntActi | Q96LT7, 108 interactors |
MINTi | Q96LT7 |
STRINGi | 9606.ENSP00000482753 |
PTM databases
iPTMneti | Q96LT7 |
PhosphoSitePlusi | Q96LT7 |
Genetic variation databases
BioMutai | C9orf72 |
DMDMi | 71152412 |
Proteomic databases
EPDi | Q96LT7 |
jPOSTi | Q96LT7 |
MassIVEi | Q96LT7 |
MaxQBi | Q96LT7 |
PaxDbi | Q96LT7 |
PeptideAtlasi | Q96LT7 |
PRIDEi | Q96LT7 |
ProteomicsDBi | 77248 [Q96LT7-1] 77249 [Q96LT7-2] |
Protocols and materials databases
Antibodypediai | 10609, 246 antibodies from 32 providers |
DNASUi | 203228 |
Genome annotation databases
Ensembli | ENST00000379995.1; ENSP00000369331.1; ENSG00000147894.17 [Q96LT7-2] ENST00000379997.7; ENSP00000369333.3; ENSG00000147894.17 [Q96LT7-2] ENST00000380003.8; ENSP00000369339.3; ENSG00000147894.17 ENST00000619707.5; ENSP00000482753.1; ENSG00000147894.17 |
GeneIDi | 203228 |
KEGGi | hsa:203228 |
MANE-Selecti | ENST00000380003.8; ENSP00000369339.3; NM_018325.5; NP_060795.1 |
UCSCi | uc003zqq.4, human [Q96LT7-1] |
Organism-specific databases
CTDi | 203228 |
DisGeNETi | 203228 |
GeneCardsi | C9orf72 |
GeneReviewsi | C9orf72 |
HGNCi | HGNC:28337, C9orf72 |
HPAi | ENSG00000147894, Low tissue specificity |
MalaCardsi | C9orf72 |
MIMi | 105550, phenotype 614260, gene |
neXtProti | NX_Q96LT7 |
OpenTargetsi | ENSG00000147894 |
Orphaneti | 803, Amyotrophic lateral sclerosis 275864, Behavioral variant of frontotemporal dementia 275872, Frontotemporal dementia with motor neuron disease 401901, Huntington disease-like syndrome due to C9ORF72 expansions 100070, Progressive non-fluent aphasia 100069, Semantic dementia |
PharmGKBi | PA134908144 |
VEuPathDBi | HostDB:ENSG00000147894 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | ENOG502QSST, Eukaryota |
GeneTreei | ENSGT00390000005644 |
HOGENOMi | CLU_047573_0_0_1 |
InParanoidi | Q96LT7 |
OMAi | IFGRSFY |
OrthoDBi | 1434762at2759 |
PhylomeDBi | Q96LT7 |
TreeFami | TF313315 |
Enzyme and pathway databases
PathwayCommonsi | Q96LT7 |
SignaLinki | Q96LT7 |
SIGNORi | Q96LT7 |
Miscellaneous databases
BioGRID-ORCSi | 203228, 12 hits in 1063 CRISPR screens |
ChiTaRSi | C9orf72, human |
GenomeRNAii | 203228 |
Pharosi | Q96LT7, Tbio |
PROi | PR:Q96LT7 |
RNActi | Q96LT7, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000147894, Expressed in monocyte and 210 other tissues |
ExpressionAtlasi | Q96LT7, baseline and differential |
Genevisiblei | Q96LT7, HS |
Family and domain databases
InterProi | View protein in InterPro IPR027819, C9orf72 |
PANTHERi | PTHR31855, PTHR31855, 1 hit |
Pfami | View protein in Pfam PF15019, C9orf72-like, 1 hit |
PROSITEi | View protein in PROSITE PS51835, DENN_C9ORF72, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | CI072_HUMAN | |
Accessioni | Q96LT7Primary (citable) accession number: Q96LT7 Secondary accession number(s): A8K5W0 Q6NUS9 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | July 19, 2005 |
Last sequence update: | July 19, 2005 | |
Last modified: | May 25, 2022 | |
This is version 149 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. |
Miscellaneousi
Keywords - Technical termi
3D-structure, Reference proteomeDocuments
- Human chromosome 9
Human chromosome 9: entries, gene names and cross-references to MIM - Human entries with genetic variants
List of human entries with genetic variants - Human variants curated from literature reports
Index of human variants curated from literature reports - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references