INSI2_PIG
ID INSI2_PIG Reviewed; 225 AA.
AC Q6PQZ3; Q5Y8D7;
DT 15-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 23-NOV-2004, sequence version 2.
DT 03-AUG-2022, entry version 58.
DE RecName: Full=Insulin-induced gene 2 protein {ECO:0000303|PubMed:15771747};
DE Short=INSIG-2 {ECO:0000303|PubMed:15771747};
GN Name=INSIG2 {ECO:0000303|PubMed:15771747};
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=15771747; DOI=10.1111/j.1365-2052.2005.01262.x;
RA Qiu H., Xia T., Chen X.D., Feng S.Q., Gan L., Lei T., Peng Y., Zhang G.D.,
RA Nie T., Yue G.P., Zhao X.L., Yang Z.Q.;
RT "Sequencing and chromosome mapping of pig INSIG 2 and a related
RT pseudogene.";
RL Anim. Genet. 36:188-189(2005).
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; AY585269; AAS99653.2; -; mRNA.
DR EMBL; AY647990; AAU88197.1; -; Genomic_DNA.
DR RefSeq; NP_001123440.1; NM_001129968.1.
DR AlphaFoldDB; Q6PQZ3; -.
DR SMR; Q6PQZ3; -.
DR PRIDE; Q6PQZ3; -.
DR Ensembl; ENSSSCT00000056159; ENSSSCP00000041204; ENSSSCG00000036229.
DR Ensembl; ENSSSCT00005052346; ENSSSCP00005032357; ENSSSCG00005032684.
DR Ensembl; ENSSSCT00025070118; ENSSSCP00025030255; ENSSSCG00025051296.
DR Ensembl; ENSSSCT00030026570; ENSSSCP00030011872; ENSSSCG00030019225.
DR Ensembl; ENSSSCT00040056038; ENSSSCP00040023298; ENSSSCG00040041867.
DR Ensembl; ENSSSCT00050046003; ENSSSCP00050018920; ENSSSCG00050034307.
DR Ensembl; ENSSSCT00055039458; ENSSSCP00055031387; ENSSSCG00055020111.
DR Ensembl; ENSSSCT00060002502; ENSSSCP00060000793; ENSSSCG00060002044.
DR Ensembl; ENSSSCT00065033210; ENSSSCP00065013712; ENSSSCG00065024855.
DR Ensembl; ENSSSCT00070004521; ENSSSCP00070003726; ENSSSCG00070002417.
DR Ensembl; ENSSSCT00070004531; ENSSSCP00070003733; ENSSSCG00070002417.
DR Ensembl; ENSSSCT00070004540; ENSSSCP00070003740; ENSSSCG00070002417.
DR Ensembl; ENSSSCT00070004550; ENSSSCP00070003749; ENSSSCG00070002417.
DR GeneID; 100170127; -.
DR KEGG; ssc:100170127; -.
DR CTD; 51141; -.
DR VGNC; VGNC:103970; INSIG2.
DR GeneTree; ENSGT00580000081600; -.
DR InParanoid; Q6PQZ3; -.
DR OMA; KHLGEPH; -.
DR OrthoDB; 1342554at2759; -.
DR Proteomes; UP000008227; Chromosome 15.
DR Proteomes; UP000314985; Chromosome 15.
DR Bgee; ENSSSCG00000036229; Expressed in metanephros cortex and 43 other tissues.
DR ExpressionAtlas; Q6PQZ3; baseline and differential.
DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; IBA:GO_Central.
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:0060363; P:cranial suture morphogenesis; IEA:Ensembl.
DR GO; GO:0042472; P:inner ear morphogenesis; IEA:Ensembl.
DR GO; GO:0042474; P:middle ear morphogenesis; IEA:Ensembl.
DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; IEA:Ensembl.
DR GO; GO:0010894; P:negative regulation of steroid biosynthetic process; IEA:Ensembl.
DR GO; GO:0060021; P:roof of mouth development; IEA:Ensembl.
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; IBA:GO_Central.
DR GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl.
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_0000286799"
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; 24791 MW; FB94A7F3B9AE2A6A CRC64;
MAEGETKSPG PKKCGPYISS VTSQSVNLMI RGVVLFFIGV FLALVLNLLQ IQRNVTLFPP
DVIASIFSSA WWVPPCCGTA SAVIGLLYPC IDRHLGEPHK FKREWSSVMR CVAVFVGINH
ASAKVDFDNN IQLSLTLAAL SIGLWWTFDR SRSGFGLGVG IAFLATLVTQ LLVYNGVYQY
TSPDFLYVRS WLPCIFFAGG ITMGNIGRQL AMYECKVIAE KSHQE
