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 24-JAN-2024, entry version 141. 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, GN 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 EMDB; EMD-30074; -. DR EMDB; EMD-31303; -. DR SMR; Q9Y5U4; -. DR BioGRID; 119325; 169. 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; 9606-ENSP00000245787; -. DR PeptideAtlas; Q9Y5U4; -. DR ProteomicsDB; 86507; -. DR Antibodypedia; 55566; 149 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 AGR; HGNC:20452; -. 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; SKKCGPY; -. DR OrthoDB; 2943928at2759; -. 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 1155 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 202 other cell types or tissues. DR ExpressionAtlas; Q9Y5U4; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProt. DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; IDA:UniProtKB. DR GO; GO:0008142; F:oxysterol binding; IDA:UniProtKB. DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProt. 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: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:0006641; P:triglyceride metabolic process; IEA:Ensembl. DR InterPro; IPR025929; INSIG_fam. DR PANTHER; PTHR15301; INSULIN-INDUCED GENE 1; 1. DR PANTHER; PTHR15301:SF10; INSULIN-INDUCED GENE 2 PROTEIN; 1. DR Pfam; PF07281; INSIG; 1. DR Genevisible; Q9Y5U4; HS. 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 //