INSI2_RAT
ID INSI2_RAT Reviewed; 225 AA.
AC Q80UA9;
DT 15-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 03-AUG-2022, entry version 99.
DE RecName: Full=Insulin-induced gene 2 protein {ECO:0000303|PubMed:12624180};
DE Short=INSIG-2 {ECO:0000303|PubMed:12624180};
GN Name=Insig2 {ECO:0000303|PubMed:12624180, ECO:0000312|RGD:631417};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND INDUCTION.
RX PubMed=12624180; DOI=10.1073/pnas.0130116100;
RA Yabe D., Komuro R., Liang G., Goldstein J.L., Brown M.S.;
RT "Liver-specific mRNA for Insig-2 down-regulated by insulin: implications
RT for fatty acid synthesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:3155-3160(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
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 22-
CC hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol and
CC 27-hydroxycholesterol, regulating interaction with SCAP and retention
CC of 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 INSIG2 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 ligase RNF139. {ECO:0000250|UniProtKB:Q9Y5U4}.
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 RNF139. Interacts with
CC RNF145. {ECO:0000250|UniProtKB:Q9Y5U4}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q9Y5U4}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9Y5U4}.
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 -!- DOMAIN: The KxHxx motif mediates association with the coatomer complex.
CC {ECO:0000250|UniProtKB:Q9Y5U4}.
CC -!- PTM: Phosphorylation at Ser-151 by PCK1 reduces binding to oxysterol,
CC disrupting the interaction between INSIG2 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:Q9Y5U4}.
CC -!- PTM: Polyubiquitinated by AMFR/gp78 at Cys-215 in some tissues such as
CC adipose tissues, undifferentiated myoblasts and liver, leading to its
CC degradation. In differentiated myotubes, Cys-215 oxidation prevents
CC ubiquitination at the same site, resulting in protein stabilization.
CC {ECO:0000250|UniProtKB:Q9Y5U4}.
CC -!- PTM: Oxidized at Cys-215 in differentiated myotubes, preventing
CC ubiquitination at the same site, and resulting in protein
CC stabilization. {ECO:0000250|UniProtKB:Q9Y5U4}.
CC -!- SIMILARITY: Belongs to the INSIG family. {ECO:0000305}.
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DR EMBL; AY152392; AAN78347.1; -; mRNA.
DR EMBL; BC085682; AAH85682.1; -; mRNA.
DR RefSeq; NP_835192.1; NM_178091.4.
DR RefSeq; XP_006249729.1; XM_006249667.3.
DR RefSeq; XP_006249730.1; XM_006249668.3.
DR RefSeq; XP_006249731.1; XM_006249669.3.
DR RefSeq; XP_017454176.1; XM_017598687.1.
DR AlphaFoldDB; Q80UA9; -.
DR SMR; Q80UA9; -.
DR STRING; 10116.ENSRNOP00000003391; -.
DR PhosphoSitePlus; Q80UA9; -.
DR PaxDb; Q80UA9; -.
DR GeneID; 288985; -.
DR KEGG; rno:288985; -.
DR UCSC; RGD:631417; rat.
DR CTD; 51141; -.
DR RGD; 631417; Insig2.
DR VEuPathDB; HostDB:ENSRNOG00000002478; -.
DR eggNOG; KOG4363; Eukaryota.
DR HOGENOM; CLU_092922_0_0_1; -.
DR InParanoid; Q80UA9; -.
DR OMA; KHLGEPH; -.
DR OrthoDB; 1342554at2759; -.
DR PhylomeDB; Q80UA9; -.
DR TreeFam; TF331013; -.
DR PRO; PR:Q80UA9; -.
DR Proteomes; UP000002494; Chromosome 13.
DR Bgee; ENSRNOG00000002478; Expressed in liver and 18 other tissues.
DR Genevisible; Q80UA9; RN.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:RGD.
DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; ISO:RGD.
DR GO; GO:0008142; F:oxysterol binding; ISS:UniProtKB.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IBA:GO_Central.
DR GO; GO:0006695; P:cholesterol biosynthetic process; ISS:UniProtKB.
DR GO; GO:0008203; P:cholesterol metabolic process; ISO:RGD.
DR GO; GO:0060363; P:cranial suture morphogenesis; ISO:RGD.
DR GO; GO:0042472; P:inner ear morphogenesis; ISO:RGD.
DR GO; GO:0042474; P:middle ear morphogenesis; ISO:RGD.
DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; ISO:RGD.
DR GO; GO:0010894; P:negative regulation of steroid biosynthetic process; ISO:RGD.
DR GO; GO:0070542; P:response to fatty acid; IEP:RGD.
DR GO; GO:0032868; P:response to insulin; IEP:RGD.
DR GO; GO:0033993; P:response to lipid; IEP:RGD.
DR GO; GO:0006991; P:response to sterol depletion; ISO:RGD.
DR GO; GO:0060021; P:roof of mouth development; ISO:RGD.
DR GO; GO:0032933; P:SREBP signaling pathway; ISS:UniProtKB.
DR GO; GO:0036316; P:SREBP-SCAP complex retention in endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0016126; P:sterol biosynthetic process; ISO:RGD.
DR GO; GO:0006641; P:triglyceride metabolic process; ISO:RGD.
DR InterPro; IPR025929; INSIG_fam.
DR PANTHER; PTHR15301; PTHR15301; 1.
DR Pfam; PF07281; INSIG; 1.
PE 2: Evidence at transcript level;
KW Cholesterol metabolism; Endoplasmic reticulum; Lipid metabolism;
KW Lipid-binding; Membrane; Oxidation; Phosphoprotein; Reference proteome;
KW Steroid metabolism; Sterol metabolism; Thioester bond; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..225
FT /note="Insulin-induced gene 2 protein"
FT /id="PRO_0000286801"
FT TOPO_DOM 1..28
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 29..51
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 52..70
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 71..88
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 89..103
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 104..126
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 127..129
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 130..148
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 149..153
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 154..175
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 176..189
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 190..207
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 208..225
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT MOTIF 219..225
FT /note="KxHxx"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT SITE 115
FT /note="Required for the recognition of 25-
FT hydroxycholesterol"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT MOD_RES 151
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT MOD_RES 215
FT /note="Cysteine sulfenic acid (-SOH); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT CROSSLNK 215
FT /note="Glycyl cysteine thioester (Cys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
SQ SEQUENCE 225 AA; 24968 MW; 534E933526CB2195 CRC64;
MAEGETESPR PKKRGPYISS VTSQSVNVVI RGVVLFFIGV FLALVLNLLQ IQRNVTLFPP
DVITSIFSSA WWVPPCCGTA SAVIGLLYPC IDRHLGEPHK FKREWSSVMR CVAVFVGINH
ASAKVDFDNN FQFSLTLAAL SVGLWWTFDR SRSGFGLGVG IAFLATVVTQ LLVYNGVYQY
TSPDFLYVRS WLPCIFFAGG ITMGNIGRQL AMYECKVIAE KSHQE
