INSI1_CRIGR
ID INSI1_CRIGR Reviewed; 257 AA.
AC Q8CFA6;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 25-MAY-2022, entry version 61.
DE RecName: Full=Insulin-induced gene 1 protein {ECO:0000303|PubMed:12242332};
DE Short=INSIG-1 {ECO:0000303|PubMed:12242332};
GN Name=INSIG1 {ECO:0000303|PubMed:12242332};
OS Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Cricetulus.
OX NCBI_TaxID=10029;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=12242332; DOI=10.1073/pnas.162488899;
RA Yabe D., Brown M.S., Goldstein J.L.;
RT "Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks
RT export of sterol regulatory element-binding proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:12753-12758(2002).
CC -!- FUNCTION: Oxysterol-binding protein that mediates feedback control of
CC cholesterol synthesis by controlling both endoplasmic reticulum to
CC Golgi transport of SCAP and degradation of HMGCR. Acts as a negative
CC regulator of cholesterol biosynthesis by mediating the retention of the
CC SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the
CC processing of sterol regulatory element-binding proteins (SREBPs)
CC SREBF1/SREBP1 and SREBF2/SREBP2. Binds oxysterol, including 25-
CC hydroxycholesterol, regulating interaction with SCAP and retention of
CC the SCAP-SREBP complex in the endoplasmic reticulum. In presence of
CC oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the
CC endoplasmic reticulum, thereby preventing SCAP from escorting
CC SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi. Sterol deprivation or
CC phosphorylation by PCK1 reduce oxysterol-binding, disrupting the
CC interaction between INSIG1 and SCAP, thereby promoting Golgi transport
CC of the SCAP-SREBP complex, followed by processing and nuclear
CC translocation of SREBF1/SREBP1 and SREBF2/SREBP2. Also regulates
CC cholesterol synthesis by regulating degradation of HMGCR: initiates the
CC sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated
CC degradation (ERAD) of HMGCR via recruitment of the reductase to the
CC ubiquitin ligases AMFR/gp78 and/or RNF139. Also regulates degradation
CC of SOAT2/ACAT2 when the lipid levels are low: initiates the ubiquitin-
CC mediated degradation of SOAT2/ACAT2 via recruitment of the ubiquitin
CC ligases AMFR/gp78. {ECO:0000250|UniProtKB:O15503}.
CC -!- SUBUNIT: Interacts with SCAP; interaction is direct and only takes
CC place in the presence of sterols; it prevents interaction between SCAP
CC and the coat protein complex II (COPII). Associates with the SCAP-SREBP
CC complex (composed of SCAP and SREBF1/SREBP1 or SREBF2/SREBP2);
CC association is mediated via its interaction with SCAP and only takes
CC place in the presence of sterols. Interacts with HMGCR (via its SSD);
CC the interaction, accelerated by sterols, leads to the recruitment of
CC HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD
CC pathway. Interacts with AMFR/gp78 (via its membrane domain); the
CC interaction recruits HMCR at the ER membrane for its ubiquitination and
CC degradation by the sterol-mediated ERAD pathway. Interacts with
CC SOAT2/ACAT2; leading to promote recruitment of AMFR/gp78 and subsequent
CC ubiquitination of SOAT2/ACAT2. Interacts with RNF139. Interacts with
CC RNF145. {ECO:0000250|UniProtKB:O15503}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:O15503}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:O15503}.
CC -!- DOMAIN: The KxHxx motif mediates association with the coatomer complex.
CC {ECO:0000250|UniProtKB:O15503}.
CC -!- DOMAIN: Binds oxysterols in a pocket within their transmembrane domains
CC and interacts with SCAP via transmembrane domains 3 and 4.
CC {ECO:0000250|UniProtKB:Q9Y5U4}.
CC -!- PTM: Phosphorylation at Ser-187 by PCK1 reduces binding to oxysterol,
CC disrupting the interaction between INSIG1 and SCAP, thereby promoting
CC nuclear translocation of SREBP proteins (SREBF1/SREBP1 or
CC SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-
CC related genes. {ECO:0000250|UniProtKB:O15503}.
CC -!- PTM: Ubiquitinated by AMFR/gp78 in response to sterol deprivation,
CC leading to its degradation: when the SCAP-SREBP complex becomes
CC dissociated from INSIG1, INSIG1 is then ubiquitinated and degraded in
CC proteasomes. Although ubiquitination is required for rapid INSIG1
CC degradation, it is not required for release of the SCAP-SREBP complex.
CC Ubiquitinated by RNF139. {ECO:0000250|UniProtKB:O15503}.
CC -!- SIMILARITY: Belongs to the INSIG family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF527628; AAN28329.1; -; mRNA.
DR RefSeq; NP_001231008.1; NM_001244079.1.
DR AlphaFoldDB; Q8CFA6; -.
DR SMR; Q8CFA6; -.
DR STRING; 10029.NP_001231008.1; -.
DR Ensembl; ENSCGRT00001014299; ENSCGRP00001010079; ENSCGRG00001012058.
DR GeneID; 100689080; -.
DR KEGG; cge:100689080; -.
DR CTD; 3638; -.
DR eggNOG; KOG4363; Eukaryota.
DR GeneTree; ENSGT00580000081600; -.
DR OrthoDB; 1342554at2759; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0008142; F:oxysterol binding; ISS:UniProtKB.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR InterPro; IPR009904; INSIG-1.
DR InterPro; IPR025929; INSIG_fam.
DR PANTHER; PTHR15301; PTHR15301; 1.
DR PANTHER; PTHR15301:SF11; PTHR15301:SF11; 1.
DR Pfam; PF07281; INSIG; 1.
PE 2: Evidence at transcript level;
KW Cholesterol metabolism; Endoplasmic reticulum; Isopeptide bond;
KW Lipid metabolism; Lipid-binding; Membrane; Phosphoprotein;
KW Steroid metabolism; Sterol metabolism; Transmembrane; Transmembrane helix;
KW Ubl conjugation.
FT CHAIN 1..257
FT /note="Insulin-induced gene 1 protein"
FT /id="PRO_0000191674"
FT TOPO_DOM 1..64
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT TRANSMEM 65..87
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 88..106
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 107..124
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 125..139
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 140..162
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 163..165
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 166..184
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 185..189
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT TRANSMEM 190..211
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 212..225
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 226..243
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 244..257
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT REGION 32..54
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 251..257
FT /note="KxHxx"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT SITE 151
FT /note="Required for the recognition of 25-
FT hydroxycholesterol"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT MOD_RES 187
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT CROSSLNK 136
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT CROSSLNK 138
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:O15503"
SQ SEQUENCE 257 AA; 27795 MW; DECE2DFE58B602AC CRC64;
MPRLHDHVWS CSGSGAARPH SLPRGMIAAA RCPQGSGAPE PAPRSPRAGT AGCGARPGSW
HHDLVQRSLV LFSFGVVLAL VLNLLQIQRN VTLFPDEVIA TIFSSAWWVP PCCGTAAAVV
GLLYPCIDSH LGEPHKFKRE WASVMRCIAV FVGINHASAK LDFANNVQLS LTLAALSLGL
WWTFDRSRSG LGLGITIAFL ATLITQFLVY NGVYQYTSPD FLYIRSWLPC IFFSGGVTVG
NIGRQLAMGV PEKPHSD
