INSIG1
entrez
3638
canonical
uniprot
O15503
canonical
ensembl
ENSG00000186480
resolver
ensp
ENSP00000340010
resolver
ensp
ENSP00000344035
resolver
ensp
ENSP00000344741
resolver
ensp
ENSP00000555595
resolver
ensp
ENSP00000555598
resolver
ensp
ENSP00000789425
resolver
enst
ENST00000344756
resolver
genesymbol
INSIG1
resolver
hgnc
HGNC:6083
resolver
uniprot
A4D2N1
resolver
uniprot
A8K6L0
resolver
uniprot
F5H6P3
resolver
uniprot
Q53XW8
resolver
uniprot
Q9BUV5
resolver
uniprot_entry
F5H6P3_HUMAN
resolver
uniprot_entry
INSI1_HUMAN
resolver
uniprot_sec
A4D2N1
resolver
uniprot_sec
A8K6L0
resolver
uniprot_sec
Q53XW8
resolver
uniprot_sec
Q9BUV5
resolver
amino_acid_sequence
MPRLHDHFWSCSCAHSARRRGPPRASAAGLAAKVGEMINVSVSGPSLLAAHGAPDADPAPRGRSAAMSGPEPGSPYPNTWHHRLLQRSLVLFSVGVVLALVLNLLQIQRNVTLFPEEVIATIFSSAWWVPPCCGTAAAVVGLLYPCIDSHLGEPHKFKREWASVMRCIAVFVGINHASAKLDFANNVQLSLTLAALSLGLWWTFDRSRSGLGLGITIAFLATLITQFLVYNGVYQYTSPDFLYIRSWLPCIFFSGGVTVGNIGRQLAMGVPEKPHSD
uniprot
proteins
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 (PubMed:12202038, PubMed:12535518, PubMed:16168377, PubMed:16399501, PubMed:16606821, PubMed:32322062). 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 (PubMed:12202038, PubMed:16399501, PubMed:26311497, PubMed:32322062). Binds oxysterol, including 25-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum (PubMed:32322062). 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 (PubMed:15899885, PubMed:32322062). 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 (PubMed:26311497, PubMed:32322062). 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 (PubMed:12535518, PubMed:16168377, PubMed:22143767). 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 (PubMed:28604676). {ECO:0000269|PubMed:12202038, ECO:0000269|PubMed:12535518, ECO:0000269|PubMed:15899885, ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:16399501, ECO:0000269|PubMed:16606821, ECO:0000269|PubMed:22143767, ECO:0000269|PubMed:26311497, ECO:0000269|PubMed:28604676, ECO:0000269|PubMed:32322062}.
uniprot
proteins
mass_dalton
29987
uniprot
proteins
mutagenesis
MUTAGEN 156; /note="K->R: Loss of ubiquitination and degradation."; /evidence="ECO:0000269|PubMed:16399501"; MUTAGEN 158; /note="K->R: Loss of ubiquitination and degradation."; /evidence="ECO:0000269|PubMed:16399501"; MUTAGEN 205; /note="D->A: Loss of ability to suppress the cleavage of SREBP2 and to accelerate the degradation of HMGCR."; /evidence="ECO:0000269|PubMed:16606821"; MUTAGEN 207; /note="S->A: Abolished phosphorylation by PCK1, does not affect oxysterol-binding, does not affect the interaction with SCAP."; /evidence="ECO:0000269|PubMed:32322062"; MUTAGEN 207; /note="S->E: Phosphomimetic mutant, reduced binding to oxysterol."; /evidence="ECO:0000269|PubMed:32322062
uniprot
proteins
post_translational_modification
PTM: Phosphorylation at Ser-207 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. {ECO:0000269|PubMed:32322062}.; PTM: 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 (PubMed:16399501, PubMed:17043353). Although ubiquitination is required for rapid INSIG1 degradation, it is not required for release of the SCAP-SREBP complex (PubMed:16399501). Ubiquitinated by RNF139 (PubMed:20068067). {ECO:0000269|PubMed:16399501, ECO:0000269|PubMed:17043353, ECO:0000269|PubMed:20068067}.
uniprot
proteins
protein_family
INSIG family
uniprot
proteins
pubmed
12202038
uniprot
proteins
pubmed
12535518
uniprot
proteins
pubmed
12690205
uniprot
proteins
pubmed
14660594
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15899885
uniprot
proteins
pubmed
16168377
uniprot
proteins
pubmed
16399501
uniprot
proteins
pubmed
16606821
uniprot
proteins
pubmed
17043353
uniprot
proteins
pubmed
20068067
uniprot
proteins
pubmed
22143767
uniprot
proteins
pubmed
23481256
uniprot
proteins
pubmed
26311497
uniprot
proteins
pubmed
28604676
uniprot
proteins
pubmed
28849786
uniprot
proteins
pubmed
29184177
uniprot
proteins
pubmed
29374057
uniprot
proteins
pubmed
32322062
uniprot
proteins
pubmed
9268630
uniprot
proteins
sequence_length
277
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:12202038, ECO:0000269|PubMed:32322062}; Multi-pass membrane protein {ECO:0000269|PubMed:12202038}.
uniprot
proteins
transmembrane_region
TRANSMEM 85..107; /note="Helical; Name=1"; /evidence="ECO:0000250|UniProtKB:A1T557"; TRANSMEM 127..144; /note="Helical; Name=2"; /evidence="ECO:0000250|UniProtKB:A1T557"; TRANSMEM 160..182; /note="Helical; Name=3"; /evidence="ECO:0000250|UniProtKB:A1T557"; TRANSMEM 186..204; /note="Helical; Name=4"; /evidence="ECO:0000250|UniProtKB:A1T557"; TRANSMEM 210..231; /note="Helical; Name=5"; /evidence="ECO:0000250|UniProtKB:A1T557"; TRANSMEM 246..263; /note="Helical; Name=6"; /evidence="ECO:0000250|UniProtKB:A1T557
uniprot
proteins