INSI2_HUMAN
ID INSI2_HUMAN Reviewed; 225 AA.
AC Q9Y5U4; A8K5W8; Q8TBI8;
DT 15-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 15-MAY-2007, sequence version 2.
DT 03-AUG-2022, entry version 133.
DE RecName: Full=Insulin-induced gene 2 protein {ECO:0000303|PubMed:12242332};
DE Short=INSIG-2 {ECO:0000303|PubMed:12242332};
GN Name=INSIG2 {ECO:0000303|PubMed:12242332, ECO:0000312|HGNC:HGNC:20452};
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 [MRNA], FUNCTION, INTERACTION WITH THE SCAP-SREBP
RP COMPLEX, AND SUBCELLULAR LOCATION.
RC TISSUE=Hypothalamus;
RX PubMed=12242332; DOI=10.1073/pnas.162488899;
RA Yabe D., Brown M.S., Goldstein J.L.;
RT "Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks
RT export of sterol regulatory element-binding proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:12753-12758(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Pituitary;
RA Bao Q., Song H., Huang Q., Dai M., Mao Y., Zhang Q., Guan Z., Luo M.,
RA Chen J., Hu R.;
RT "Homo sapiens insulin induced protein 2 mRNA.";
RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [7]
RP MUTAGENESIS OF GLU-214.
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 [8]
RP FUNCTION, AND MUTAGENESIS OF ASP-149.
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 [9]
RP FUNCTION, INTERACTION WITH SCAP, LIPID-BINDING, DOMAIN, AND MUTAGENESIS OF
RP PHE-115; GLN-132; THR-136; TRP-145 AND ASP-149.
RX PubMed=17428920; DOI=10.1073/pnas.0700899104;
RA Radhakrishnan A., Ikeda Y., Kwon H.J., Brown M.S., Goldstein J.L.;
RT "Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi:
RT oxysterols block transport by binding to Insig.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:6511-6518(2007).
RN [10]
RP INTERACTION WITH 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 [11]
RP FUNCTION, LIPID-BINDING, INTERACTION WITH SCAP, DOMAIN, AND MUTAGENESIS OF
RP GLY-39; CYS-77; ALA-113; VAL-114; PHE-115; VAL-116; GLY-117; HIS-120;
RP GLN-132; TRP-145; ASP-149 AND GLY-200.
RX PubMed=26160948; DOI=10.1126/science.aab1091;
RA Ren R., Zhou X., He Y., Ke M., Wu J., Liu X., Yan C., Wu Y., Gong X.,
RA Lei X., Yan S.F., Radhakrishnan A., Yan N.;
RT "Crystal structure of a mycobacterial Insig homolog provides insight into
RT how these sensors monitor sterol levels.";
RL Science 349:187-191(2015).
RN [12]
RP FUNCTION, AND INTERACTION WITH 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 [13]
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 [14]
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 [15]
RP FUNCTION, LIPID-BINDING, SUBCELLULAR LOCATION, INTERACTION WITH SCAP,
RP PHOSPHORYLATION AT SER-151, AND MUTAGENESIS OF SER-151.
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 [16]
RP UBIQUITINATION AT CYS-215, OXIDATION AT CYS-215, AND MUTAGENESIS OF
RP 100-LYS--LYS-102 AND CYS-215.
RX PubMed=31953408; DOI=10.1038/s41467-019-14231-w;
RA Zhou Z.S., Li M.X., Liu J., Jiao H., Xia J.M., Shi X.J., Zhao H., Chu L.,
RA Liu J., Qi W., Luo J., Song B.L.;
RT "Competitive oxidation and ubiquitylation on the evolutionarily conserved
RT cysteine confer tissue-specific stabilization of Insig-2.";
RL Nat. Commun. 11:379-379(2020).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.46 ANGSTROMS) OF 221-225, 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:12242332,
CC PubMed:16606821, PubMed:32322062). Acts as a negative regulator of
CC cholesterol biosynthesis by mediating the retention of the SCAP-SREBP
CC complex in the endoplasmic reticulum, thereby blocking the processing
CC of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1
CC and SREBF2/SREBP2 (PubMed:32322062). 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
CC (PubMed:26160948, PubMed:17428920, PubMed:32322062). 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 (PubMed:32322062). Sterol
CC deprivation or phosphorylation by PCK1 reduce oxysterol-binding,
CC disrupting the interaction between INSIG2 and SCAP, thereby promoting
CC Golgi transport of the SCAP-SREBP complex, followed by processing and
CC nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2
CC (PubMed:32322062). Also regulates cholesterol synthesis by regulating
CC degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated
CC endoplasmic reticulum-associated degradation (ERAD) of HMGCR via
CC recruitment of the reductase to the ubiquitin ligase RNF139
CC (PubMed:16606821, PubMed:22143767). {ECO:0000269|PubMed:12242332,
CC ECO:0000269|PubMed:16606821, ECO:0000269|PubMed:17428920,
CC ECO:0000269|PubMed:22143767, ECO:0000269|PubMed:26160948,
CC 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:12242332,
CC PubMed:17428920, PubMed:26160948, PubMed:32322062). Associates with the
CC SCAP-SREBP complex (composed of SCAP and SREBF1/SREBP1 or
CC SREBF2/SREBP2); association is mediated via its interaction with SCAP
CC and only takes place in the presence of sterols (PubMed:12242332,
CC PubMed:32322062). Interacts with RNF139 (PubMed:20068067,
CC PubMed:22143767). Interacts with RNF145 (PubMed:29374057).
CC {ECO:0000269|PubMed:12242332, ECO:0000269|PubMed:17428920,
CC ECO:0000269|PubMed:20068067, ECO:0000269|PubMed:22143767,
CC ECO:0000269|PubMed:26160948, ECO:0000269|PubMed:29374057,
CC ECO:0000269|PubMed:32322062}.
CC -!- INTERACTION:
CC Q9Y5U4; Q8TB40: ABHD4; NbExp=3; IntAct=EBI-8503746, EBI-7131019;
CC Q9Y5U4; P41181: AQP2; NbExp=3; IntAct=EBI-8503746, EBI-12701138;
CC Q9Y5U4; Q13520: AQP6; NbExp=3; IntAct=EBI-8503746, EBI-13059134;
CC Q9Y5U4; Q99437: ATP6V0B; NbExp=3; IntAct=EBI-8503746, EBI-3904417;
CC Q9Y5U4; Q13323: BIK; NbExp=3; IntAct=EBI-8503746, EBI-700794;
CC Q9Y5U4; P25942: CD40; NbExp=3; IntAct=EBI-8503746, EBI-525714;
CC Q9Y5U4; P11912: CD79A; NbExp=3; IntAct=EBI-8503746, EBI-7797864;
CC Q9Y5U4; Q7Z7G2: CPLX4; NbExp=3; IntAct=EBI-8503746, EBI-18013275;
CC Q9Y5U4; Q96BA8: CREB3L1; NbExp=3; IntAct=EBI-8503746, EBI-6942903;
CC Q9Y5U4; Q9BQA9: CYBC1; NbExp=3; IntAct=EBI-8503746, EBI-2680384;
CC Q9Y5U4; Q15125: EBP; NbExp=3; IntAct=EBI-8503746, EBI-3915253;
CC Q9Y5U4; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-8503746, EBI-18304435;
CC Q9Y5U4; P48165: GJA8; NbExp=3; IntAct=EBI-8503746, EBI-17458373;
CC Q9Y5U4; Q8NBJ4: GOLM1; NbExp=3; IntAct=EBI-8503746, EBI-712073;
CC Q9Y5U4; Q8TDT2: GPR152; NbExp=3; IntAct=EBI-8503746, EBI-13345167;
CC Q9Y5U4; O60883: GPR37L1; NbExp=3; IntAct=EBI-8503746, EBI-2927498;
CC Q9Y5U4; Q8TED1: GPX8; NbExp=3; IntAct=EBI-8503746, EBI-11721746;
CC Q9Y5U4; Q7Z5P4: HSD17B13; NbExp=3; IntAct=EBI-8503746, EBI-18053395;
CC Q9Y5U4; P38484: IFNGR2; NbExp=3; IntAct=EBI-8503746, EBI-3905457;
CC Q9Y5U4; P43628: KIR2DL3; NbExp=3; IntAct=EBI-8503746, EBI-8632435;
CC Q9Y5U4; Q13571: LAPTM5; NbExp=3; IntAct=EBI-8503746, EBI-2865663;
CC Q9Y5U4; Q8TAF8: LHFPL5; NbExp=3; IntAct=EBI-8503746, EBI-2820517;
CC Q9Y5U4; Q8N4V1: MMGT1; NbExp=3; IntAct=EBI-8503746, EBI-6163737;
CC Q9Y5U4; P15941-11: MUC1; NbExp=3; IntAct=EBI-8503746, EBI-17263240;
CC Q9Y5U4; O14524-2: NEMP1; NbExp=3; IntAct=EBI-8503746, EBI-10969203;
CC Q9Y5U4; P16471: PRLR; NbExp=3; IntAct=EBI-8503746, EBI-476182;
CC Q9Y5U4; P15151: PVR; NbExp=3; IntAct=EBI-8503746, EBI-3919694;
CC Q9Y5U4; Q99942: RNF5; NbExp=6; IntAct=EBI-8503746, EBI-348482;
CC Q9Y5U4; Q9NY72: SCN3B; NbExp=3; IntAct=EBI-8503746, EBI-17247926;
CC Q9Y5U4; Q8TF71: SLC16A10; NbExp=3; IntAct=EBI-8503746, EBI-17858931;
CC Q9Y5U4; Q13586: STIM1; NbExp=3; IntAct=EBI-8503746, EBI-448878;
CC Q9Y5U4; Q9NUH8: TMEM14B; NbExp=3; IntAct=EBI-8503746, EBI-8638294;
CC Q9Y5U4; Q96Q45-2: TMEM237; NbExp=4; IntAct=EBI-8503746, EBI-10982110;
CC Q9Y5U4; Q96B21: TMEM45B; NbExp=3; IntAct=EBI-8503746, EBI-3923061;
CC Q9Y5U4; Q4KMG9: TMEM52B; NbExp=3; IntAct=EBI-8503746, EBI-18178701;
CC Q9Y5U4; Q9Y320: TMX2; NbExp=3; IntAct=EBI-8503746, EBI-6447886;
CC Q9Y5U4; Q3ZAQ7: VMA21; NbExp=3; IntAct=EBI-8503746, EBI-1055364;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:12242332, ECO:0000269|PubMed:32322062}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:12242332}.
CC -!- DOMAIN: Binds oxysterols in a pocket within their transmembrane domains
CC and interacts with SCAP via transmembrane domains 3 and 4.
CC {ECO:0000269|PubMed:17428920, ECO:0000269|PubMed:26160948}.
CC -!- DOMAIN: The KxHxx motif mediates association with the coatomer complex.
CC {ECO:0000269|PubMed:23481256}.
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:0000269|PubMed:32322062}.
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 (PubMed:31953408). In differentiated myotubes, Cys-215
CC oxidation prevents ubiquitination at the same site, resulting in
CC protein stabilization (PubMed:31953408). {ECO:0000269|PubMed:31953408}.
CC -!- PTM: Oxidized at Cys-215 in differentiated myotubes, preventing
CC ubiquitination at the same site, and resulting in protein
CC stabilization. {ECO:0000269|PubMed:31953408}.
CC -!- SIMILARITY: Belongs to the INSIG family. {ECO:0000305}.
CC -!- CAUTION: A study showed that INSIG2 is not ubiquitinated by AMFR/gp78
CC (PubMed:17043353). However, another paper showed that it is
CC ubiquitinated on Cys-215, and that ubiquitination takes place in some
CC tissues only and depends on the differentiation state
CC (PubMed:31953408). {ECO:0000269|PubMed:17043353,
CC ECO:0000269|PubMed:31953408}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD43048.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AF527632; AAN28333.1; -; mRNA.
DR EMBL; AF125392; AAD43048.1; ALT_FRAME; mRNA.
DR EMBL; AK291433; BAF84122.1; -; mRNA.
DR EMBL; AC009303; AAX93280.1; -; Genomic_DNA.
DR EMBL; CH471103; EAW95199.1; -; Genomic_DNA.
DR EMBL; BC022475; AAH22475.1; -; mRNA.
DR CCDS; CCDS2122.1; -.
DR RefSeq; NP_001308258.1; NM_001321329.1.
DR RefSeq; NP_001308259.1; NM_001321330.1.
DR RefSeq; NP_001308260.1; NM_001321331.1.
DR RefSeq; NP_001308261.1; NM_001321332.1.
DR RefSeq; NP_001308262.1; NM_001321333.1.
DR RefSeq; NP_057217.2; NM_016133.3.
DR PDB; 4J82; X-ray; 1.46 A; C/D=221-225.
DR PDB; 6M49; EM; 3.70 A; A=1-225.
DR PDB; 7ETW; EM; 4.10 A; A=1-225.
DR PDBsum; 4J82; -.
DR PDBsum; 6M49; -.
DR PDBsum; 7ETW; -.
DR AlphaFoldDB; Q9Y5U4; -.
DR SMR; Q9Y5U4; -.
DR BioGRID; 119325; 168.
DR DIP; DIP-60913N; -.
DR IntAct; Q9Y5U4; 42.
DR MINT; Q9Y5U4; -.
DR STRING; 9606.ENSP00000245787; -.
DR TCDB; 9.B.418.1.1; the insulin-induced gene 1 & 2 protein (insig) family.
DR iPTMnet; Q9Y5U4; -.
DR PhosphoSitePlus; Q9Y5U4; -.
DR BioMuta; INSIG2; -.
DR DMDM; 147646722; -.
DR MassIVE; Q9Y5U4; -.
DR MaxQB; Q9Y5U4; -.
DR PaxDb; Q9Y5U4; -.
DR PeptideAtlas; Q9Y5U4; -.
DR PRIDE; Q9Y5U4; -.
DR ProteomicsDB; 86507; -.
DR Antibodypedia; 55566; 123 antibodies from 26 providers.
DR DNASU; 51141; -.
DR Ensembl; ENST00000245787.9; ENSP00000245787.4; ENSG00000125629.16.
DR GeneID; 51141; -.
DR KEGG; hsa:51141; -.
DR MANE-Select; ENST00000245787.9; ENSP00000245787.4; NM_016133.4; NP_057217.2.
DR UCSC; uc002tlk.4; human.
DR CTD; 51141; -.
DR DisGeNET; 51141; -.
DR GeneCards; INSIG2; -.
DR HGNC; HGNC:20452; INSIG2.
DR HPA; ENSG00000125629; Low tissue specificity.
DR MIM; 608660; gene.
DR neXtProt; NX_Q9Y5U4; -.
DR OpenTargets; ENSG00000125629; -.
DR PharmGKB; PA134890284; -.
DR VEuPathDB; HostDB:ENSG00000125629; -.
DR eggNOG; KOG4363; Eukaryota.
DR GeneTree; ENSGT00580000081600; -.
DR HOGENOM; CLU_092922_0_0_1; -.
DR InParanoid; Q9Y5U4; -.
DR OMA; KHLGEPH; -.
DR OrthoDB; 1342554at2759; -.
DR PhylomeDB; Q9Y5U4; -.
DR TreeFam; TF331013; -.
DR PathwayCommons; Q9Y5U4; -.
DR Reactome; R-HSA-1655829; Regulation of cholesterol biosynthesis by SREBP (SREBF).
DR SignaLink; Q9Y5U4; -.
DR SIGNOR; Q9Y5U4; -.
DR BioGRID-ORCS; 51141; 14 hits in 1077 CRISPR screens.
DR ChiTaRS; INSIG2; human.
DR GeneWiki; INSIG2; -.
DR GenomeRNAi; 51141; -.
DR Pharos; Q9Y5U4; Tbio.
DR PRO; PR:Q9Y5U4; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q9Y5U4; protein.
DR Bgee; ENSG00000125629; Expressed in right coronary artery and 200 other tissues.
DR ExpressionAtlas; Q9Y5U4; baseline and differential.
DR Genevisible; Q9Y5U4; 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:0006695; P:cholesterol biosynthetic process; 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: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:0070542; P:response to fatty acid; 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; IPR025929; INSIG_fam.
DR PANTHER; PTHR15301; PTHR15301; 1.
DR Pfam; PF07281; INSIG; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cholesterol metabolism; Endoplasmic reticulum;
KW Lipid metabolism; Lipid-binding; Membrane; Oxidation; Phosphoprotein;
KW Reference proteome; Steroid metabolism; Sterol metabolism; Thioester bond;
KW Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..225
FT /note="Insulin-induced gene 2 protein"
FT /id="PRO_0000286797"
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:0000269|PubMed:23481256"
FT SITE 115
FT /note="Required for the recognition of 25-
FT hydroxycholesterol"
FT /evidence="ECO:0000269|PubMed:17428920"
FT MOD_RES 151
FT /note="Phosphoserine; by PCK1"
FT /evidence="ECO:0000269|PubMed:32322062"
FT MOD_RES 215
FT /note="Cysteine sulfenic acid (-SOH); alternate"
FT /evidence="ECO:0000269|PubMed:31953408"
FT CROSSLNK 215
FT /note="Glycyl cysteine thioester (Cys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000269|PubMed:31953408"
FT MUTAGEN 39
FT /note="G->F: Decreased binding to 25-hydroxycholesterol,
FT leading to decreased interaction with SCAP."
FT /evidence="ECO:0000269|PubMed:26160948"
FT MUTAGEN 77
FT /note="C->D: Decreased binding to 25-hydroxycholesterol,
FT leading to decreased interaction with SCAP."
FT /evidence="ECO:0000269|PubMed:26160948"
FT MUTAGEN 100..102
FT /note="KFK->RFR: Does not affect degradation of the
FT protein."
FT /evidence="ECO:0000269|PubMed:31953408"
FT MUTAGEN 113
FT /note="A->W: Abolished interaction with SCAP even in the
FT presence of 25-hydroxycholesterol."
FT /evidence="ECO:0000269|PubMed:26160948"
FT MUTAGEN 114
FT /note="V->F: Does not affect interaction with SCAP."
FT /evidence="ECO:0000269|PubMed:26160948"
FT MUTAGEN 115
FT /note="F->A: Decreased binding to 25-hydroxycholesterol and
FT subsequent interaction with SCAP."
FT /evidence="ECO:0000269|PubMed:17428920,
FT ECO:0000269|PubMed:26160948"
FT MUTAGEN 116
FT /note="V->F: Does not affect interaction with SCAP."
FT /evidence="ECO:0000269|PubMed:26160948"
FT MUTAGEN 117
FT /note="G->F: Abolished interaction with SCAP even in the
FT presence of 25-hydroxycholesterol."
FT /evidence="ECO:0000269|PubMed:26160948"
FT MUTAGEN 120
FT /note="H->F: Abolished interaction with SCAP even in the
FT presence of 25-hydroxycholesterol."
FT /evidence="ECO:0000269|PubMed:26160948"
FT MUTAGEN 132
FT /note="Q->A: Abolished interaction with SCAP without
FT affecting binding to 25-hydroxycholesterol."
FT /evidence="ECO:0000269|PubMed:17428920,
FT ECO:0000269|PubMed:26160948"
FT MUTAGEN 136
FT /note="T->A: Decreased binding to 25-hydroxycholesterol and
FT subsequent interaction with SCAP."
FT /evidence="ECO:0000269|PubMed:17428920"
FT MUTAGEN 145
FT /note="W->A: Abolished interaction with SCAP without
FT affecting binding to 25-hydroxycholesterol."
FT /evidence="ECO:0000269|PubMed:17428920,
FT ECO:0000269|PubMed:26160948"
FT MUTAGEN 149
FT /note="D->A: Loss of ability to suppress the cleavage of
FT SREBP2 and to accelerate the degradation of HMGCR.
FT Abolished interaction with SCAP without affecting binding
FT to 25-hydroxycholesterol."
FT /evidence="ECO:0000269|PubMed:16606821,
FT ECO:0000269|PubMed:17428920, ECO:0000269|PubMed:26160948"
FT MUTAGEN 151
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 151
FT /note="S->E: Phosphomimetic mutant, reduced binding to
FT oxysterol."
FT /evidence="ECO:0000269|PubMed:32322062"
FT MUTAGEN 200
FT /note="G->F: Decreased binding to 25-hydroxycholesterol,
FT leading to decreased interaction with SCAP."
FT /evidence="ECO:0000269|PubMed:26160948"
FT MUTAGEN 214
FT /note="E->A: Promotes ubiquitination by AMFR/gp78, which
FT does not take place normally."
FT /evidence="ECO:0000269|PubMed:17043353"
FT MUTAGEN 215
FT /note="C->A: Prevents degradation because of impaired
FT ubiquitination."
FT /evidence="ECO:0000269|PubMed:31953408"
SQ SEQUENCE 225 AA; 24778 MW; 13E0392F1B30F08C CRC64;
MAEGETESPG PKKCGPYISS VTSQSVNLMI RGVVLFFIGV FLALVLNLLQ IQRNVTLFPP
DVIASIFSSA WWVPPCCGTA SAVIGLLYPC IDRHLGEPHK FKREWSSVMR CVAVFVGINH
ASAKVDFDNN IQLSLTLAAL SIGLWWTFDR SRSGFGLGVG IAFLATVVTQ LLVYNGVYQY
TSPDFLYVRS WLPCIFFAGG ITMGNIGRQL AMYECKVIAE KSHQE
