INSI2_CALJA
ID INSI2_CALJA Reviewed; 225 AA.
AC B0CMA4;
DT 10-JUN-2008, integrated into UniProtKB/Swiss-Prot.
DT 26-FEB-2008, sequence version 1.
DT 03-AUG-2022, entry version 69.
DE RecName: Full=Insulin-induced gene 2 protein {ECO:0000250|UniProtKB:Q9Y5U4};
DE Short=INSIG-2 {ECO:0000250|UniProtKB:Q9Y5U4};
GN Name=INSIG2 {ECO:0000250|UniProtKB:Q9Y5U4};
OS Callithrix jacchus (White-tufted-ear marmoset).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Platyrrhini; Cebidae;
OC Callitrichinae; Callithrix; Callithrix.
OX NCBI_TaxID=9483;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Antonellis A., Benjamin B., Blakesley R.W., Bouffard G.G., Brinkley C.,
RA Brooks S., Chu G., Chub I., Coleman H., Fuksenko T., Gestole M.,
RA Gregory M., Guan X., Gupta J., Gurson N., Han E., Han J., Hansen N.,
RA Hargrove A., Hines-Harris K., Ho S.-L., Hu P., Hunter G., Hurle B.,
RA Idol J.R., Johnson T., Knight E., Kwong P., Lee-Lin S.-Q., Legaspi R.,
RA Madden M., Maduro Q.L., Maduro V.B., Margulies E.H., Masiello C.,
RA Maskeri B., McDowell J., Merkulov G., Montemayor C., Mullikin J.C.,
RA Park M., Prasad A., Ramsahoye C., Reddix-Dugue N., Riebow N., Schandler K.,
RA Schueler M.G., Sison C., Smith L., Stantripop S., Thomas J.W., Thomas P.J.,
RA Tsipouri V., Young A., Green E.D.;
RT "NISC comparative sequencing initiative.";
RL Submitted (JAN-2008) to the EMBL/GenBank/DDBJ databases.
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; DP000561; ABY74565.1; -; Genomic_DNA.
DR RefSeq; XP_008997259.1; XM_008999011.2.
DR RefSeq; XP_017829018.1; XM_017973529.1.
DR AlphaFoldDB; B0CMA4; -.
DR SMR; B0CMA4; -.
DR STRING; 9483.ENSCJAP00000048422; -.
DR Ensembl; ENSCJAT00000105743; ENSCJAP00000078937; ENSCJAG00000021424.
DR GeneID; 100400887; -.
DR KEGG; cjc:100400887; -.
DR CTD; 51141; -.
DR eggNOG; KOG4363; Eukaryota.
DR GeneTree; ENSGT00580000081600; -.
DR HOGENOM; CLU_092922_0_0_1; -.
DR InParanoid; B0CMA4; -.
DR OMA; KHLGEPH; -.
DR OrthoDB; 1342554at2759; -.
DR TreeFam; TF331013; -.
DR Proteomes; UP000008225; Chromosome 6.
DR Bgee; ENSCJAG00000021424; Expressed in liver and 6 other tissues.
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:0006695; P:cholesterol biosynthetic process; ISS:UniProtKB.
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 InterPro; IPR025929; INSIG_fam.
DR PANTHER; PTHR15301; PTHR15301; 1.
DR Pfam; PF07281; INSIG; 1.
PE 3: Inferred from homology;
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_0000339169"
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; 24891 MW; 8C09CBF199AA5175 CRC64;
MVEEETESPG PKKCGPYISS VTSQSVNLMI RGVVLFFIGV FLALVLNLLQ IQRNVTLFPP
DVIASIFSSA WWVPPCCGTA SAVIGLLYPC IDRHLGEPHK FNREWSNVMR CVAVFVGINH
ASAKLDFDNN IQLSLTLAAL SVGLWWTFDR SRSGFGLGVG IAFLATVVTQ LLVYNGVYQY
TSPDFLYVRS WLPCIFFAGG ITMGNIGRQL AMYECKVIAE KSHQE
