INSI1_HUMAN
ID INSI1_HUMAN Reviewed; 277 AA.
AC O15503; A4D2N1; A8K6L0; Q53XW8; Q9BUV5;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2006, sequence version 3.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=Insulin-induced gene 1 protein {ECO:0000303|PubMed:12202038, ECO:0000303|PubMed:9268630};
DE Short=INSIG-1 {ECO:0000303|PubMed:12202038};
GN Name=INSIG1 {ECO:0000303|PubMed:9268630, ECO:0000312|HGNC:HGNC:6083};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-27, AND INDUCTION.
RX PubMed=9268630; DOI=10.1006/geno.1997.4821;
RA Peng Y., Schwarz E.J., Lazar M.A., Genin A., Spinner N.B., Taub R.;
RT "Cloning, human chromosomal assignment, and adipose and hepatic expression
RT of the CL-6/INSIG1 gene.";
RL Genomics 43:278-284(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 40-61 AND
RP 64-83, IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, SUBCELLULAR LOCATION,
RP TISSUE SPECIFICITY, AND INTERACTION WITH SCAP AND SREBP2 COMPLEX.
RX PubMed=12202038; DOI=10.1016/s0092-8674(02)00872-3;
RA Yang T., Espenshade P.J., Wright M.E., Yabe D., Gong Y., Aebersold R.,
RA Goldstein J.L., Brown M.S.;
RT "Crucial step in cholesterol homeostasis: sterols promote binding of SCAP
RT to INSIG-1, a membrane protein that facilitates retention of SREBPs in
RT ER.";
RL Cell 110:489-500(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Mammary tumor;
RA Birkett C., Cho J., Gau Y., Hamer R., Kelly S., Kovacs K., Liu L., Liu X.,
RA Porter J., Sachs A., Shu Y., Sun Z., Wong J., Wu M., Zhang X., Jay G.,
RA He W.;
RT "High-throughput cloning of full-length human cDNAs directly from cDNA
RT libraries optimized for large and rare transcripts.";
RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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).
RN [9]
RP INTERACTION WITH HMGCR, AND FUNCTION.
RX PubMed=12535518; DOI=10.1016/s1097-2765(02)00822-5;
RA Sever N., Yang T., Brown M.S., Goldstein J.L., DeBose-Boyd R.A.;
RT "Accelerated degradation of HMG CoA reductase mediated by binding of insig-
RT 1 to its sterol-sensing domain.";
RL Mol. Cell 11:25-33(2003).
RN [10]
RP TOPOLOGY.
RX PubMed=14660594; DOI=10.1074/jbc.m312623200;
RA Feramisco J.D., Goldstein J.L., Brown M.S.;
RT "Membrane topology of human insig-1, a protein regulator of lipid
RT synthesis.";
RL J. Biol. Chem. 279:8487-8496(2004).
RN [11]
RP FUNCTION, AND INTERACTION WITH SCAP.
RX PubMed=15899885; DOI=10.1074/jbc.m504041200;
RA Sun L.-P., Li L., Goldstein J.L., Brown M.S.;
RT "Insig required for sterol-mediated inhibition of Scap/SREBP binding to
RT COPII proteins in vitro.";
RL J. Biol. Chem. 280:26483-26490(2005).
RN [12]
RP INTERACTION WITH AMFR, AND FUNCTION.
RX PubMed=16168377; DOI=10.1016/j.molcel.2005.08.009;
RA Song B.L., Sever N., DeBose-Boyd R.A.;
RT "Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and
RT couples sterol-regulated ubiquitination to degradation of HMG CoA
RT reductase.";
RL Mol. Cell 19:829-840(2005).
RN [13]
RP FUNCTION, INTERACTION WITH SCAP AND SREBP2 COMPLEX, UBIQUITINATION AT
RP LYS-156 AND LYS-158, AND MUTAGENESIS OF LYS-156 AND LYS-158.
RX PubMed=16399501; DOI=10.1016/j.cmet.2005.11.014;
RA Gong Y., Lee J.N., Lee P.C., Goldstein J.L., Brown M.S., Ye J.;
RT "Sterol-regulated ubiquitination and degradation of Insig-1 creates a
RT convergent mechanism for feedback control of cholesterol synthesis and
RT uptake.";
RL Cell Metab. 3:15-24(2006).
RN [14]
RP UBIQUITINATION.
RX PubMed=17043353; DOI=10.1074/jbc.m608999200;
RA Lee J.N., Song B., DeBose-Boyd R.A., Ye J.;
RT "Sterol-regulated degradation of Insig-1 mediated by the membrane-bound
RT ubiquitin ligase gp78.";
RL J. Biol. Chem. 281:39308-39315(2006).
RN [15]
RP FUNCTION, AND MUTAGENESIS OF ASP-205.
RX PubMed=16606821; DOI=10.1073/pnas.0601923103;
RA Gong Y., Lee J.N., Brown M.S., Goldstein J.L., Ye J.;
RT "Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for
RT cholesterol homeostasis.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:6154-6159(2006).
RN [16]
RP INTERACTION WITH RNF139, AND UBIQUITINATION BY RNF139.
RX PubMed=20068067; DOI=10.1158/1541-7786.mcr-08-0491;
RA Lee J.P., Brauweiler A., Rudolph M., Hooper J.E., Drabkin H.A.,
RA Gemmill R.M.;
RT "The TRC8 ubiquitin ligase is sterol regulated and interacts with lipid and
RT protein biosynthetic pathways.";
RL Mol. Cancer Res. 8:93-106(2010).
RN [17]
RP FUNCTION, AND INTERACTION WITH AMFR AND RNF139.
RX PubMed=22143767; DOI=10.1073/pnas.1112831108;
RA Jo Y., Lee P.C., Sguigna P.V., DeBose-Boyd R.A.;
RT "Sterol-induced degradation of HMG CoA reductase depends on interplay of
RT two Insigs and two ubiquitin ligases, gp78 and Trc8.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:20503-20508(2011).
RN [18]
RP FUNCTION, AND INTERACTION WITH SOAT2.
RX PubMed=28604676; DOI=10.1038/ncb3551;
RA Wang Y.J., Bian Y., Luo J., Lu M., Xiong Y., Guo S.Y., Yin H.Y., Lin X.,
RA Li Q., Chang C.C.Y., Chang T.Y., Li B.L., Song B.L.;
RT "Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2
RT through competitive oxidation.";
RL Nat. Cell Biol. 19:808-819(2017).
RN [19]
RP ERRATUM OF PUBMED:28604676.
RX PubMed=29184177; DOI=10.1038/ncb3651;
RA Wang Y.J., Bian Y., Luo J., Lu M., Xiong Y., Guo S.Y., Yong H., Lin X.,
RA Li Q., Chang C.C.Y., Chang T.Y., Li B.L., Song B.L.;
RT "Corrigendum: Cholesterol and fatty acids regulate cysteine ubiquitylation
RT of ACAT2 through competitive oxidation.";
RL Nat. Cell Biol. 19:1441-1441(2017).
RN [20]
RP REVIEW.
RX PubMed=28849786; DOI=10.1038/nrendo.2017.91;
RA Shimano H., Sato R.;
RT "SREBP-regulated lipid metabolism: convergent physiology - divergent
RT pathophysiology.";
RL Nat. Rev. Endocrinol. 13:710-730(2017).
RN [21]
RP INTERACTION WITH RNF145.
RX PubMed=29374057; DOI=10.1074/jbc.ra117.001260;
RA Jiang L.Y., Jiang W., Tian N., Xiong Y.N., Liu J., Wei J., Wu K.Y., Luo J.,
RA Shi X.J., Song B.L.;
RT "Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced
RT degradation of HMG-CoA reductase.";
RL J. Biol. Chem. 293:4047-4055(2018).
RN [22]
RP FUNCTION, LIPID-BINDING, SUBCELLULAR LOCATION, INTERACTION WITH SCAP,
RP PHOSPHORYLATION AT SER-207, AND MUTAGENESIS OF SER-207.
RX PubMed=32322062; DOI=10.1038/s41586-020-2183-2;
RA Xu D., Wang Z., Xia Y., Shao F., Xia W., Wei Y., Li X., Qian X., Lee J.H.,
RA Du L., Zheng Y., Lv G., Leu J.S., Wang H., Xing D., Liang T., Hung M.C.,
RA Lu Z.;
RT "The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis.";
RL Nature 580:530-535(2020).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.74 ANGSTROMS) OF 273-277, AND DOMAIN.
RX PubMed=23481256; DOI=10.1038/emboj.2013.41;
RA Ma W., Goldberg J.;
RT "Rules for the recognition of dilysine retrieval motifs by coatomer.";
RL EMBO J. 32:926-937(2013).
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 (PubMed:12202038,
CC PubMed:12535518, PubMed:16168377, PubMed:16399501, PubMed:16606821,
CC PubMed:32322062). Acts as a negative regulator of cholesterol
CC biosynthesis by mediating the retention of the SCAP-SREBP complex in
CC the endoplasmic reticulum, thereby blocking the processing of sterol
CC regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and
CC SREBF2/SREBP2 (PubMed:12202038, PubMed:16399501, PubMed:32322062).
CC Binds oxysterol, including 25-hydroxycholesterol, regulating
CC interaction with SCAP and retention of the SCAP-SREBP complex in the
CC endoplasmic reticulum (PubMed:32322062). In presence of oxysterol,
CC 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 (PubMed:15899885,
CC PubMed:32322062). Sterol deprivation or phosphorylation by PCK1 reduce
CC oxysterol-binding, disrupting the interaction between INSIG1 and SCAP,
CC thereby promoting Golgi transport of the SCAP-SREBP complex, followed
CC by processing and nuclear translocation of SREBF1/SREBP1 and
CC SREBF2/SREBP2 (PubMed:32322062). Also regulates cholesterol synthesis
CC by regulating degradation of HMGCR: initiates the sterol-mediated
CC ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD)
CC of HMGCR via recruitment of the reductase to the ubiquitin ligases
CC AMFR/gp78 and/or RNF139 (PubMed:12535518, PubMed:16168377,
CC PubMed:22143767). Also regulates degradation of SOAT2/ACAT2 when the
CC lipid levels are low: initiates the ubiquitin-mediated degradation of
CC SOAT2/ACAT2 via recruitment of the ubiquitin ligases AMFR/gp78
CC (PubMed:28604676). {ECO:0000269|PubMed:12202038,
CC ECO:0000269|PubMed:12535518, ECO:0000269|PubMed:15899885,
CC ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:16399501,
CC ECO:0000269|PubMed:16606821, ECO:0000269|PubMed:22143767,
CC ECO:0000269|PubMed:28604676, ECO:0000269|PubMed:32322062}.
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) (PubMed:15899885,
CC PubMed:32322062). Associates with the SCAP-SREBP complex (composed of
CC SCAP and SREBF1/SREBP1 or SREBF2/SREBP2); association is mediated via
CC its interaction with SCAP and only takes place in the presence of
CC sterols (PubMed:12202038, PubMed:16399501, PubMed:32322062). Interacts
CC with HMGCR (via its SSD); the interaction, accelerated by sterols,
CC leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination
CC by the sterol-mediated ERAD pathway (PubMed:12535518). Interacts with
CC AMFR/gp78 (via its membrane domain); the interaction recruits HMCR at
CC the ER membrane for its ubiquitination and degradation by the sterol-
CC mediated ERAD pathway (PubMed:16168377, PubMed:22143767). Interacts
CC with SOAT2/ACAT2; leading to promote recruitment of AMFR/gp78 and
CC subsequent ubiquitination of SOAT2/ACAT2 (PubMed:28604676). Interacts
CC with RNF139 (PubMed:20068067, PubMed:22143767). Interacts with RNF145
CC (PubMed:29374057). {ECO:0000269|PubMed:12202038,
CC ECO:0000269|PubMed:12535518, ECO:0000269|PubMed:15899885,
CC ECO:0000269|PubMed:16168377, ECO:0000269|PubMed:16399501,
CC ECO:0000269|PubMed:20068067, ECO:0000269|PubMed:22143767,
CC ECO:0000269|PubMed:28604676, ECO:0000269|PubMed:29374057,
CC ECO:0000269|PubMed:32322062}.
CC -!- INTERACTION:
CC O15503; Q9UKV5: AMFR; NbExp=2; IntAct=EBI-6252425, EBI-1046367;
CC O15503; Q13520: AQP6; NbExp=3; IntAct=EBI-6252425, EBI-13059134;
CC O15503; Q96Q45-2: TMEM237; NbExp=3; IntAct=EBI-6252425, EBI-10982110;
CC O15503; P00180: CYP2C1; Xeno; NbExp=2; IntAct=EBI-6252425, EBI-6251821;
CC O15503; P00181: CYP2C2; Xeno; NbExp=3; IntAct=EBI-6252425, EBI-4320576;
CC O15503; P00347: HMGCR; Xeno; NbExp=2; IntAct=EBI-6252425, EBI-11426687;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:12202038, ECO:0000269|PubMed:32322062}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:12202038}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O15503-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O15503-2; Sequence=VSP_045084, VSP_045085;
CC -!- TISSUE SPECIFICITY: Expressed in all tissues tested with highest
CC expression in the liver. {ECO:0000269|PubMed:12202038}.
CC -!- INDUCTION: By insulin (PubMed:9268630). Expressed at high levels when
CC nuclear SREBP levels are high as a result of sterol deprivation
CC (PubMed:16399501). {ECO:0000269|PubMed:16399501,
CC ECO:0000269|PubMed:9268630}.
CC -!- DOMAIN: The KxHxx motif mediates association with the coatomer complex.
CC {ECO:0000269|PubMed:23481256}.
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-207 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:0000269|PubMed:32322062}.
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 (PubMed:16399501, PubMed:17043353). Although ubiquitination
CC is required for rapid INSIG1 degradation, it is not required for
CC release of the SCAP-SREBP complex (PubMed:16399501). Ubiquitinated by
CC RNF139 (PubMed:20068067). {ECO:0000269|PubMed:16399501,
CC ECO:0000269|PubMed:17043353, ECO:0000269|PubMed:20068067}.
CC -!- SIMILARITY: Belongs to the INSIG family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Insig1 entry;
CC URL="https://en.wikipedia.org/wiki/Insig1";
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DR EMBL; U96876; AAB69121.1; -; Genomic_DNA.
DR EMBL; AY112745; AAM44086.1; -; mRNA.
DR EMBL; BT007227; AAP35891.1; -; mRNA.
DR EMBL; AK291675; BAF84364.1; -; mRNA.
DR EMBL; DN996424; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC144652; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC231970; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH236962; EAL23729.1; -; Genomic_DNA.
DR EMBL; CH236962; EAL23730.1; -; Genomic_DNA.
DR EMBL; CH471149; EAX04529.1; -; Genomic_DNA.
DR EMBL; CH471149; EAX04530.1; -; Genomic_DNA.
DR EMBL; BC001880; AAH01880.1; -; mRNA.
DR CCDS; CCDS5938.1; -. [O15503-1]
DR CCDS; CCDS5939.1; -. [O15503-2]
DR RefSeq; NP_001333519.1; NM_001346590.1.
DR RefSeq; NP_001333520.1; NM_001346591.1.
DR RefSeq; NP_001333521.1; NM_001346592.1. [O15503-1]
DR RefSeq; NP_001333522.1; NM_001346593.1. [O15503-2]
DR RefSeq; NP_001333523.1; NM_001346594.1.
DR RefSeq; NP_005533.2; NM_005542.5. [O15503-1]
DR RefSeq; NP_938150.2; NM_198336.3.
DR RefSeq; NP_938151.1; NM_198337.3. [O15503-2]
DR RefSeq; XP_016867666.1; XM_017012177.1.
DR PDB; 4J81; X-ray; 1.74 A; C/D=273-277.
DR PDBsum; 4J81; -.
DR AlphaFoldDB; O15503; -.
DR SMR; O15503; -.
DR BioGRID; 109850; 126.
DR CORUM; O15503; -.
DR DIP; DIP-61157N; -.
DR IntAct; O15503; 16.
DR MINT; O15503; -.
DR STRING; 9606.ENSP00000344741; -.
DR ChEMBL; CHEMBL4739841; -.
DR TCDB; 9.B.418.1.2; the insulin-induced gene 1 & 2 protein (insig) family.
DR iPTMnet; O15503; -.
DR PhosphoSitePlus; O15503; -.
DR BioMuta; INSIG1; -.
DR EPD; O15503; -.
DR MassIVE; O15503; -.
DR PaxDb; O15503; -.
DR PeptideAtlas; O15503; -.
DR PRIDE; O15503; -.
DR ProteomicsDB; 48699; -. [O15503-1]
DR ProteomicsDB; 647; -.
DR Antibodypedia; 33108; 223 antibodies from 21 providers.
DR DNASU; 3638; -.
DR Ensembl; ENST00000340368.9; ENSP00000344741.4; ENSG00000186480.13. [O15503-1]
DR Ensembl; ENST00000342407.5; ENSP00000344035.5; ENSG00000186480.13. [O15503-2]
DR GeneID; 3638; -.
DR KEGG; hsa:3638; -.
DR MANE-Select; ENST00000340368.9; ENSP00000344741.4; NM_005542.6; NP_005533.2.
DR UCSC; uc003wly.3; human. [O15503-1]
DR CTD; 3638; -.
DR DisGeNET; 3638; -.
DR GeneCards; INSIG1; -.
DR HGNC; HGNC:6083; INSIG1.
DR HPA; ENSG00000186480; Tissue enriched (liver).
DR MIM; 602055; gene.
DR neXtProt; NX_O15503; -.
DR OpenTargets; ENSG00000186480; -.
DR PharmGKB; PA29890; -.
DR VEuPathDB; HostDB:ENSG00000186480; -.
DR eggNOG; KOG4363; Eukaryota.
DR GeneTree; ENSGT00580000081600; -.
DR HOGENOM; CLU_092922_0_0_1; -.
DR InParanoid; O15503; -.
DR OMA; FWSCSCT; -.
DR OrthoDB; 1342554at2759; -.
DR PhylomeDB; O15503; -.
DR TreeFam; TF331013; -.
DR PathwayCommons; O15503; -.
DR Reactome; R-HSA-1655829; Regulation of cholesterol biosynthesis by SREBP (SREBF).
DR SignaLink; O15503; -.
DR SIGNOR; O15503; -.
DR BioGRID-ORCS; 3638; 18 hits in 1077 CRISPR screens.
DR ChiTaRS; INSIG1; human.
DR GeneWiki; INSIG1; -.
DR GenomeRNAi; 3638; -.
DR Pharos; O15503; Tbio.
DR PRO; PR:O15503; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; O15503; protein.
DR Bgee; ENSG00000186480; Expressed in cartilage tissue and 205 other tissues.
DR ExpressionAtlas; O15503; baseline and differential.
DR Genevisible; O15503; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; IDA:UniProtKB.
DR GO; GO:0008142; F:oxysterol binding; IDA:UniProtKB.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IBA:GO_Central.
DR GO; GO:0036315; P:cellular response to sterol; IMP:UniProtKB.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IDA:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; IDA: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:1901303; P:negative regulation of cargo loading into COPII-coated vesicle; IMP:UniProtKB.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; IEA:Ensembl.
DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; IEA:Ensembl.
DR GO; GO:0070862; P:negative regulation of protein exit from endoplasmic reticulum; IDA:UniProtKB.
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; IDA:UniProtKB.
DR GO; GO:0036316; P:SREBP-SCAP complex retention in endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl.
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 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cholesterol metabolism;
KW Direct protein sequencing; Endoplasmic reticulum; Isopeptide bond;
KW Lipid metabolism; Lipid-binding; Membrane; Phosphoprotein;
KW Reference proteome; Steroid metabolism; Sterol metabolism; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..277
FT /note="Insulin-induced gene 1 protein"
FT /id="PRO_0000191675"
FT TOPO_DOM 1..84
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:14660594"
FT TRANSMEM 85..107
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 108..126
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 127..144
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 145..159
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 160..182
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 183..185
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 186..204
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 205..209
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:14660594"
FT TRANSMEM 210..231
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 232..245
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 246..263
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 264..277
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:14660594"
FT REGION 51..73
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 271..277
FT /note="KxHxx"
FT /evidence="ECO:0000269|PubMed:23481256"
FT SITE 171
FT /note="Required for the recognition of 25-
FT hydroxycholesterol"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT MOD_RES 207
FT /note="Phosphoserine; by PCK1"
FT /evidence="ECO:0000269|PubMed:32322062"
FT CROSSLNK 156
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:16399501"
FT CROSSLNK 158
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:16399501"
FT VAR_SEQ 138..164
FT /note="AVVGLLYPCIDSHLGEPHKFKREWASV -> GIHPQISSIFVLGSLVYFSQE
FT ASRWGT (in isoform 2)"
FT /evidence="ECO:0000303|Ref.5"
FT /id="VSP_045084"
FT VAR_SEQ 165..277
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.5"
FT /id="VSP_045085"
FT VARIANT 27
FT /note="A -> T (in dbSNP:rs1129825)"
FT /evidence="ECO:0000269|PubMed:9268630"
FT /id="VAR_027683"
FT MUTAGEN 156
FT /note="K->R: Loss of ubiquitination and degradation."
FT /evidence="ECO:0000269|PubMed:16399501"
FT MUTAGEN 158
FT /note="K->R: Loss of ubiquitination and degradation."
FT /evidence="ECO:0000269|PubMed:16399501"
FT MUTAGEN 205
FT /note="D->A: Loss of ability to suppress the cleavage of
FT SREBP2 and to accelerate the degradation of HMGCR."
FT /evidence="ECO:0000269|PubMed:16606821"
FT MUTAGEN 207
FT /note="S->A: Abolished phosphorylation by PCK1, does not
FT affect oxysterol-binding, does not affect the interaction
FT with SCAP."
FT /evidence="ECO:0000269|PubMed:32322062"
FT MUTAGEN 207
FT /note="S->E: Phosphomimetic mutant, reduced binding to
FT oxysterol."
FT /evidence="ECO:0000269|PubMed:32322062"
FT CONFLICT 31..32
FT /note="AA -> PP (in Ref. 1; AAB69121)"
FT /evidence="ECO:0000305"
FT CONFLICT 99
FT /note="A -> T (in Ref. 1; AAB69121)"
FT /evidence="ECO:0000305"
FT CONFLICT 170..172
FT /note="VFV -> GFG (in Ref. 1; AAB69121)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 277 AA; 29987 MW; 198068D53C658A58 CRC64;
MPRLHDHFWS CSCAHSARRR GPPRASAAGL AAKVGEMINV SVSGPSLLAA HGAPDADPAP
RGRSAAMSGP EPGSPYPNTW HHRLLQRSLV LFSVGVVLAL VLNLLQIQRN VTLFPEEVIA
TIFSSAWWVP PCCGTAAAVV GLLYPCIDSH LGEPHKFKRE WASVMRCIAV FVGINHASAK
LDFANNVQLS LTLAALSLGL WWTFDRSRSG LGLGITIAFL ATLITQFLVY NGVYQYTSPD
FLYIRSWLPC IFFSGGVTVG NIGRQLAMGV PEKPHSD
