INSIG2
entrez
51141
canonical
uniprot
Q9Y5U4
canonical
ensembl
ENSG00000125629
resolver
ensp
ENSP00000245787
resolver
ensp
ENSP00000534829
resolver
ensp
ENSP00000534830
resolver
ensp
ENSP00000534831
resolver
ensp
ENSP00000534833
resolver
ensp
ENSP00000534834
resolver
ensp
ENSP00000604847
resolver
ensp
ENSP00000621529
resolver
enst
ENST00000245787
resolver
enst
ENST00000864770
resolver
enst
ENST00000864771
resolver
enst
ENST00000864772
resolver
enst
ENST00000864774
resolver
enst
ENST00000864775
resolver
enst
ENST00000934788
resolver
enst
ENST00000951470
resolver
genesymbol
INSIG2
resolver
hgnc
HGNC:20452
resolver
uniprot
A8K5W8
resolver
uniprot
B4DQ23
resolver
uniprot
Q8TBI8
resolver
uniprot_entry
B4DQ23_HUMAN
resolver
uniprot_entry
INSI2_HUMAN
resolver
uniprot_sec
A8K5W8
resolver
uniprot_sec
Q8TBI8
resolver
amino_acid_sequence
MAEGETESPGPKKCGPYISSVTSQSVNLMIRGVVLFFIGVFLALVLNLLQIQRNVTLFPPDVIASIFSSAWWVPPCCGTASAVIGLLYPCIDRHLGEPHKFKREWSSVMRCVAVFVGINHASAKVDFDNNIQLSLTLAALSIGLWWTFDRSRSGFGLGVGIAFLATVVTQLLVYNGVYQYTSPDFLYVRSWLPCIFFAGGITMGNIGRQLAMYECKVIAEKSHQE
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:12242332, 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:32322062). Binds oxysterol, including 22-hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum (PubMed:17428920, PubMed:26160948, 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:32322062). Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG2 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2 (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 ligase RNF139 (PubMed:16606821, PubMed:22143767). {ECO:0000269|PubMed:12242332, ECO:0000269|PubMed:16606821, ECO:0000269|PubMed:17428920, ECO:0000269|PubMed:22143767, ECO:0000269|PubMed:26160948, ECO:0000269|PubMed:32322062}.
uniprot
proteins
mass_dalton
24778
uniprot
proteins
mutagenesis
MUTAGEN 39; /note="G->F: Decreased binding to 25-hydroxycholesterol, leading to decreased interaction with SCAP."; /evidence="ECO:0000269|PubMed:26160948"; MUTAGEN 77; /note="C->D: Decreased binding to 25-hydroxycholesterol, leading to decreased interaction with SCAP."; /evidence="ECO:0000269|PubMed:26160948"; MUTAGEN 100..102; /note="KFK->RFR: Does not affect degradation of the protein."; /evidence="ECO:0000269|PubMed:31953408"; MUTAGEN 113; /note="A->W: Abolished interaction with SCAP even in the presence of 25-hydroxycholesterol."; /evidence="ECO:0000269|PubMed:26160948"; MUTAGEN 114; /note="V->F: Does not affect interaction with SCAP."; /evidence="ECO:0000269|PubMed:26160948"; MUTAGEN 115; /note="F->A: Decreased binding to 25-hydroxycholesterol and subsequent interaction with SCAP."; /evidence="ECO:0000269|PubMed:17428920, ECO:0000269|PubMed:26160948"; MUTAGEN 116; /note="V->F: Does not affect interaction with SCAP."; /evidence="ECO:0000269|PubMed:26160948"; MUTAGEN 117; /note="G->F: Abolished interaction with SCAP even in the presence of 25-hydroxycholesterol."; /evidence="ECO:0000269|PubMed:26160948"; MUTAGEN 120; /note="H->F: Abolished interaction with SCAP even in the presence of 25-hydroxycholesterol."; /evidence="ECO:0000269|PubMed:26160948"; MUTAGEN 132; /note="Q->A: Abolished interaction with SCAP without affecting binding to 25-hydroxycholesterol."; /evidence="ECO:0000269|PubMed:17428920, ECO:0000269|PubMed:26160948"; MUTAGEN 136; /note="T->A: Decreased binding to 25-hydroxycholesterol and subsequent interaction with SCAP."; /evidence="ECO:0000269|PubMed:17428920"; MUTAGEN 145; /note="W->A: Abolished interaction with SCAP without affecting binding to 25-hydroxycholesterol."; /evidence="ECO:0000269|PubMed:17428920, ECO:0000269|PubMed:26160948"; MUTAGEN 149; /note="D->A: Loss of ability to suppress the cleavage of SREBP2 and to accelerate the degradation of HMGCR. Abolished interaction with SCAP without affecting binding to 25-hydroxycholesterol."; /evidence="ECO:0000269|PubMed:16606821, ECO:0000269|PubMed:17428920, ECO:0000269|PubMed:26160948"; MUTAGEN 151; /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 151; /note="S->E: Phosphomimetic mutant, reduced binding to oxysterol."; /evidence="ECO:0000269|PubMed:32322062"; MUTAGEN 200; /note="G->F: Decreased binding to 25-hydroxycholesterol, leading to decreased interaction with SCAP."; /evidence="ECO:0000269|PubMed:26160948"; MUTAGEN 214; /note="E->A: Promotes ubiquitination by AMFR/gp78, which does not take place normally."; /evidence="ECO:0000269|PubMed:17043353"; MUTAGEN 215; /note="C->A: Prevents degradation because of impaired ubiquitination."; /evidence="ECO:0000269|PubMed:31953408
uniprot
proteins
post_translational_modification
PTM: Phosphorylation at Ser-151 by PCK1 reduces binding to oxysterol, disrupting the interaction between INSIG2 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: Polyubiquitinated by AMFR/gp78 at Cys-215 in some tissues such as adipose tissues, undifferentiated myoblasts and liver, leading to its degradation (PubMed:31953408). In differentiated myotubes, Cys-215 oxidation prevents ubiquitination at the same site, resulting in protein stabilization (PubMed:31953408). {ECO:0000269|PubMed:31953408}.; PTM: Oxidized at Cys-215 in differentiated myotubes, preventing ubiquitination at the same site, and resulting in protein stabilization. {ECO:0000269|PubMed:31953408}.
uniprot
proteins
protein_family
INSIG family
uniprot
proteins
pubmed
12242332
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15815621
uniprot
proteins
pubmed
16606821
uniprot
proteins
pubmed
17043353
uniprot
proteins
pubmed
17428920
uniprot
proteins
pubmed
20068067
uniprot
proteins
pubmed
22143767
uniprot
proteins
pubmed
23481256
uniprot
proteins
pubmed
26160948
uniprot
proteins
pubmed
28849786
uniprot
proteins
pubmed
29374057
uniprot
proteins
pubmed
31953408
uniprot
proteins
pubmed
32322062
uniprot
proteins
sequence_length
225
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000269|PubMed:12242332, ECO:0000269|PubMed:32322062}; Multi-pass membrane protein {ECO:0000269|PubMed:12242332}.
uniprot
proteins
transmembrane_region
TRANSMEM 29..51; /note="Helical; Name=1"; /evidence="ECO:0000250|UniProtKB:A1T557"; TRANSMEM 71..88; /note="Helical; Name=2"; /evidence="ECO:0000250|UniProtKB:A1T557"; TRANSMEM 104..126; /note="Helical; Name=3"; /evidence="ECO:0000250|UniProtKB:A1T557"; TRANSMEM 130..148; /note="Helical; Name=4"; /evidence="ECO:0000250|UniProtKB:A1T557"; TRANSMEM 154..175; /note="Helical; Name=5"; /evidence="ECO:0000250|UniProtKB:A1T557"; TRANSMEM 190..207; /note="Helical; Name=6"; /evidence="ECO:0000250|UniProtKB:A1T557
uniprot
proteins