Q8CFA6 · INSI1_CRIGR
- ProteinInsulin-induced gene 1 protein
- GeneINSIG1
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids257 (go to sequence)
- Protein existenceEvidence at transcript level
- Annotation score3/5
Function
function
Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR. Acts as a negative regulator of cholesterol biosynthesis by mediating the retention of the SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2. Binds oxysterol, including 25-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum. In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the endoplasmic reticulum, thereby preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi. Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG1 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2. Also regulates cholesterol synthesis by regulating degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligases AMFR/gp78 and/or RNF139. Also regulates degradation of SOAT2/ACAT2 when the lipid levels are low: initiates the ubiquitin-mediated degradation of SOAT2/ACAT2 via recruitment of the ubiquitin ligases AMFR/gp78.
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 151 | Required for the recognition of 25-hydroxycholesterol | ||||
Sequence: F |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | SREBP-SCAP-Insig complex | |
Molecular Function | oxysterol binding | |
Biological Process | cellular response to insulin stimulus | |
Biological Process | cholesterol biosynthetic process | |
Biological Process | SREBP signaling pathway | |
Biological Process | SREBP-SCAP complex retention in endoplasmic reticulum |
Keywords
- Biological process
- Ligand
Names & Taxonomy
Protein names
- Recommended nameInsulin-induced gene 1 protein
- Short namesINSIG-1
Gene names
Organism names
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Cricetidae > Cricetinae > Cricetulus
Accessions
- Primary accessionQ8CFA6
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Endoplasmic reticulum membrane ; Multi-pass membrane protein
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-64 | Cytoplasmic | ||||
Sequence: MPRLHDHVWSCSGSGAARPHSLPRGMIAAARCPQGSGAPEPAPRSPRAGTAGCGARPGSWHHDL | ||||||
Transmembrane | 65-87 | Helical; Name=1 | ||||
Sequence: VQRSLVLFSFGVVLALVLNLLQI | ||||||
Topological domain | 88-106 | Extracellular | ||||
Sequence: QRNVTLFPDEVIATIFSSA | ||||||
Transmembrane | 107-124 | Helical; Name=2 | ||||
Sequence: WWVPPCCGTAAAVVGLLY | ||||||
Topological domain | 125-139 | Cytoplasmic | ||||
Sequence: PCIDSHLGEPHKFKR | ||||||
Transmembrane | 140-162 | Helical; Name=3 | ||||
Sequence: EWASVMRCIAVFVGINHASAKLD | ||||||
Topological domain | 163-165 | Extracellular | ||||
Sequence: FAN | ||||||
Transmembrane | 166-184 | Helical; Name=4 | ||||
Sequence: NVQLSLTLAALSLGLWWTF | ||||||
Topological domain | 185-189 | Cytoplasmic | ||||
Sequence: DRSRS | ||||||
Transmembrane | 190-211 | Helical; Name=5 | ||||
Sequence: GLGLGITIAFLATLITQFLVYN | ||||||
Topological domain | 212-225 | Extracellular | ||||
Sequence: GVYQYTSPDFLYIR | ||||||
Transmembrane | 226-243 | Helical; Name=6 | ||||
Sequence: SWLPCIFFSGGVTVGNIG | ||||||
Topological domain | 244-257 | Cytoplasmic | ||||
Sequence: RQLAMGVPEKPHSD |
Keywords
- Cellular component
PTM/Processing
Features
Showing features for chain, cross-link, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000191674 | 1-257 | Insulin-induced gene 1 protein | |||
Sequence: MPRLHDHVWSCSGSGAARPHSLPRGMIAAARCPQGSGAPEPAPRSPRAGTAGCGARPGSWHHDLVQRSLVLFSFGVVLALVLNLLQIQRNVTLFPDEVIATIFSSAWWVPPCCGTAAAVVGLLYPCIDSHLGEPHKFKREWASVMRCIAVFVGINHASAKLDFANNVQLSLTLAALSLGLWWTFDRSRSGLGLGITIAFLATLITQFLVYNGVYQYTSPDFLYIRSWLPCIFFSGGVTVGNIGRQLAMGVPEKPHSD | ||||||
Cross-link | 136 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Cross-link | 138 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 187 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylation at Ser-187 by PCK1 reduces binding to oxysterol, disrupting the interaction between INSIG1 and SCAP, thereby promoting nuclear translocation of SREBP proteins (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-related genes.
Ubiquitinated by AMFR/gp78 in response to sterol deprivation, leading to its degradation: when the SCAP-SREBP complex becomes dissociated from INSIG1, INSIG1 is then ubiquitinated and degraded in proteasomes. Although ubiquitination is required for rapid INSIG1 degradation, it is not required for release of the SCAP-SREBP complex. Ubiquitinated by RNF139.
Keywords
- PTM
Proteomic databases
Interaction
Subunit
Interacts with SCAP; interaction is direct and only takes place in the presence of sterols; it prevents interaction between SCAP and the coat protein complex II (COPII). Associates with the SCAP-SREBP complex (composed of SCAP and SREBF1/SREBP1 or SREBF2/SREBP2); association is mediated via its interaction with SCAP and only takes place in the presence of sterols. Interacts with HMGCR (via its SSD); the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway. Interacts with AMFR/gp78 (via its membrane domain); the interaction recruits HMCR at the ER membrane for its ubiquitination and degradation by the sterol-mediated ERAD pathway. Interacts with SOAT2/ACAT2; leading to promote recruitment of AMFR/gp78 and subsequent ubiquitination of SOAT2/ACAT2. Interacts with RNF139. Interacts with RNF145.
Structure
Family & Domains
Features
Showing features for region, motif.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 32-54 | Disordered | ||||
Sequence: CPQGSGAPEPAPRSPRAGTAGCG | ||||||
Motif | 251-257 | KxHxx | ||||
Sequence: PEKPHSD |
Domain
The KxHxx motif mediates association with the coatomer complex.
Binds oxysterols in a pocket within their transmembrane domains and interacts with SCAP via transmembrane domains 3 and 4.
Sequence similarities
Belongs to the INSIG family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length257
- Mass (Da)27,795
- Last updated2003-03-01 v1
- ChecksumDECE2DFE58B602AC
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF527628 EMBL· GenBank· DDBJ | AAN28329.1 EMBL· GenBank· DDBJ | mRNA |