Q8CFA6 · INSI1_CRIGR

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.

125720406080100120140160180200220240
TypeIDPosition(s)Description
Site151Required for the recognition of 25-hydroxycholesterol

GO annotations

AspectTerm
Cellular ComponentSREBP-SCAP-Insig complex
Molecular Functionoxysterol binding
Biological Processcellular response to insulin stimulus
Biological Processcholesterol biosynthetic process
Biological ProcessSREBP signaling pathway
Biological ProcessSREBP-SCAP complex retention in endoplasmic reticulum

Keywords

Names & Taxonomy

Protein names

  • Recommended name
    Insulin-induced gene 1 protein
  • Short names
    INSIG-1

Gene names

    • Name
      INSIG1

Organism names

Accessions

  • Primary accession
    Q8CFA6

Proteomes

Subcellular Location

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain1-64Cytoplasmic
Transmembrane65-87Helical; Name=1
Topological domain88-106Extracellular
Transmembrane107-124Helical; Name=2
Topological domain125-139Cytoplasmic
Transmembrane140-162Helical; Name=3
Topological domain163-165Extracellular
Transmembrane166-184Helical; Name=4
Topological domain185-189Cytoplasmic
Transmembrane190-211Helical; Name=5
Topological domain212-225Extracellular
Transmembrane226-243Helical; Name=6
Topological domain244-257Cytoplasmic

Keywords

PTM/Processing

Features

Showing features for chain, cross-link, modified residue.

TypeIDPosition(s)Description
ChainPRO_00001916741-257Insulin-induced gene 1 protein
Cross-link136Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Cross-link138Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Modified residue187Phosphoserine

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

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.

TypeIDPosition(s)Description
Region32-54Disordered
Motif251-257KxHxx

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

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    257
  • Mass (Da)
    27,795
  • Last updated
    2003-03-01 v1
  • Checksum
    DECE2DFE58B602AC
MPRLHDHVWSCSGSGAARPHSLPRGMIAAARCPQGSGAPEPAPRSPRAGTAGCGARPGSWHHDLVQRSLVLFSFGVVLALVLNLLQIQRNVTLFPDEVIATIFSSAWWVPPCCGTAAAVVGLLYPCIDSHLGEPHKFKREWASVMRCIAVFVGINHASAKLDFANNVQLSLTLAALSLGLWWTFDRSRSGLGLGITIAFLATLITQFLVYNGVYQYTSPDFLYIRSWLPCIFFSGGVTVGNIGRQLAMGVPEKPHSD

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AF527628
EMBL· GenBank· DDBJ
AAN28329.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

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