INSI2_PONAB
ID INSI2_PONAB Reviewed; 225 AA.
AC Q5R687;
DT 15-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 12-AUG-2020, sequence version 3.
DT 03-AUG-2022, entry version 52.
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 Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3-225.
RC TISSUE=Brain cortex;
RG The German cDNA consortium;
RL Submitted (NOV-2004) 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}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAH92729.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305};
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DR EMBL; CR860607; CAH92729.1; ALT_SEQ; mRNA.
DR RefSeq; XP_009235931.1; XM_009237656.1.
DR AlphaFoldDB; Q5R687; -.
DR SMR; Q5R687; -.
DR STRING; 9601.ENSPPYP00000014277; -.
DR Ensembl; ENSPPYT00000045300; ENSPPYP00000027018; ENSPPYG00000037275.
DR eggNOG; KOG4363; Eukaryota.
DR GeneTree; ENSGT00580000081600; -.
DR InParanoid; Q5R687; -.
DR Proteomes; UP000001595; Chromosome 2B.
DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; IEA:Ensembl.
DR GO; GO:0008142; F:oxysterol binding; ISS:UniProtKB.
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: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_0000286800"
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; 24777 MW; FB94BDE9B9B4306A CRC64;
MAEGETKSPG PKKCGPYISS VTSQSVNLMI RGVVLFFIGV FLALVLNLLQ IQRNVTLFPP
DVIASIFSSA WWVPPCCGTA SAVIGLLYPC IDRHLGEPHK FKREWSSVMR CVAVFVGINH
ASAKVDFDNN IQLSLTLAAL SIGLWWTFDR SRSGFGLGVG IAFLATVVTQ LLVYNGVYQY
TSPDFLYVRS WLPCIFFAGG ITMGNIGRQL AMYECKVIAE KSHQE
