SRBP2_HUMAN
ID SRBP2_HUMAN Reviewed; 1141 AA.
AC Q12772; Q05BD5; Q6GTH7; Q86V36; Q9UH04;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 215.
DE RecName: Full=Sterol regulatory element-binding protein 2 {ECO:0000303|PubMed:15461802};
DE Short=SREBP-2 {ECO:0000303|PubMed:15461802};
DE AltName: Full=Class D basic helix-loop-helix protein 2;
DE Short=bHLHd2;
DE AltName: Full=Sterol regulatory element-binding transcription factor 2 {ECO:0000303|PubMed:15461802};
DE Contains:
DE RecName: Full=Processed sterol regulatory element-binding protein 2 {ECO:0000305};
DE AltName: Full=Transcription factor SREBF2 {ECO:0000305};
GN Name=SREBF2 {ECO:0000303|PubMed:32322062, ECO:0000312|HGNC:HGNC:11290};
GN Synonyms=BHLHD2, SREBP2 {ECO:0000303|PubMed:15461802};
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] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, AND
RP VARIANT ALA-595.
RX PubMed=7903453; DOI=10.1073/pnas.90.24.11603;
RA Hua X., Yokoyama C., Wu J., Briggs M.R., Brown M.S., Goldstein J.L.,
RA Wang X.;
RT "SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that
RT stimulates transcription by binding to a sterol regulatory element.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:11603-11607(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M.,
RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E.,
RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A.,
RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Lymph, and 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 [5]
RP PROTEIN SEQUENCE OF 91-109.
RX PubMed=8402897; DOI=10.1016/s0092-8674(05)80095-9;
RA Yokoyama C., Wang X., Briggs M.R., Admon A., Wu J., Hua X., Goldstein J.L.,
RA Brown M.S.;
RT "SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls
RT transcription of the low density lipoprotein receptor gene.";
RL Cell 75:187-197(1993).
RN [6]
RP SUBCELLULAR LOCATION, AND UBIQUITINATION.
RX PubMed=11477106; DOI=10.1074/jbc.m105200200;
RA Hirano Y., Yoshida M., Shimizu M., Sato R.;
RT "Direct demonstration of rapid degradation of nuclear sterol regulatory
RT element-binding proteins by the ubiquitin-proteasome pathway.";
RL J. Biol. Chem. 276:36431-36437(2001).
RN [7]
RP SUBCELLULAR LOCATION.
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 [8]
RP FUNCTION, AND MUTAGENESIS OF TYR-342.
RX PubMed=12177166;
RA Amemiya-Kudo M., Shimano H., Hasty A.H., Yahagi N., Yoshikawa T.,
RA Matsuzaka T., Okazaki H., Tamura Y., Iizuka Y., Ohashi K., Osuga J.,
RA Harada K., Gotoda T., Sato R., Kimura S., Ishibashi S., Yamada N.;
RT "Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different
RT target promoters of lipogenic and cholesterogenic genes.";
RL J. Lipid Res. 43:1220-1235(2002).
RN [9]
RP PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF ASP-478; ARG-519 AND
RP 478-ASP--ARG-481.
RX PubMed=8626610; DOI=10.1074/jbc.271.17.10379;
RA Hua X., Sakai J., Brown M.S., Goldstein J.L.;
RT "Regulated cleavage of sterol regulatory element binding proteins requires
RT sequences on both sides of the endoplasmic reticulum membrane.";
RL J. Biol. Chem. 271:10379-10384(1996).
RN [10]
RP PROTEOLYTIC CLEAVAGE AT ASP-468 BY CASPASES.
RX PubMed=8643593; DOI=10.1073/pnas.93.11.5437;
RA Pai J.-T., Brown M.S., Goldstein J.L.;
RT "Purification and cDNA cloning of a second apoptosis-related cysteine
RT protease that cleaves and activates sterol regulatory element binding
RT proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:5437-5442(1996).
RN [11]
RP PROTEOLYTIC CLEAVAGE AT LEU-484 BY S2P, AND MUTAGENESIS OF ARG-479;
RP ARG-481; LEU-484; CYS-485; 478-ASP--ARG-481; 479-ARG--ARG-481 AND
RP 484-LEU-CYS-485.
RX PubMed=9651382; DOI=10.1074/jbc.273.28.17801;
RA Duncan E.A., Dave U.P., Sakai J., Goldstein J.L., Brown M.S.;
RT "Second-site cleavage in sterol regulatory element-binding protein occurs
RT at transmembrane junction as determined by cysteine panning.";
RL J. Biol. Chem. 273:17801-17809(1998).
RN [12]
RP PROTEOLYTIC CLEAVAGE AT LEU-484 BY S2P, PROTEOLYTIC CLEAVAGE AT LEU-522 BY
RP S1P, AND MUTAGENESIS OF ASN-495; PRO-496; 490-LEU-CYS-491 AND
RP 495-ASN-PRO-496.
RX PubMed=10805775; DOI=10.1073/pnas.97.10.5123;
RA Ye J., Dave U.P., Grishin N.V., Goldstein J.L., Brown M.S.;
RT "Asparagine-proline sequence within membrane-spanning segment of SREBP
RT triggers intramembrane cleavage by site-2 protease.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:5123-5128(2000).
RN [13]
RP INTERACTION WITH RNF139.
RX PubMed=19706601; DOI=10.1074/jbc.m109.041376;
RA Irisawa M., Inoue J., Ozawa N., Mori K., Sato R.;
RT "The sterol-sensing endoplasmic reticulum (ER) membrane protein TRC8
RT hampers ER to Golgi transport of sterol regulatory element-binding protein-
RT 2 (SREBP-2)/SREBP cleavage-activated protein and reduces SREBP-2
RT cleavage.";
RL J. Biol. Chem. 284:28995-29004(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-855 AND SER-1098, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [15]
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 [16]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-464, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [17]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH SCAP, AND PROTEOLYTIC
RP CLEAVAGE.
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 [18]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 343-403.
RX PubMed=14645851; DOI=10.1126/science.1088372;
RA Lee S.J., Sekimoto T., Yamashita E., Nagoshi E., Nakagawa A., Imamoto N.,
RA Yoshimura M., Sakai H., Chong K.T., Tsukihara T., Yoneda Y.;
RT "The structure of importin-beta bound to SREBP-2: nuclear import of a
RT transcription factor.";
RL Science 302:1571-1575(2003).
RN [19]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-273 AND LYS-347.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: [Sterol regulatory element-binding protein 2]: Precursor of
CC the transcription factor form (Processed sterol regulatory element-
CC binding protein 2), which is embedded in the endoplasmic reticulum
CC membrane (PubMed:32322062). Low sterol concentrations promote
CC processing of this form, releasing the transcription factor form that
CC translocates into the nucleus and activates transcription of genes
CC involved in cholesterol biosynthesis (PubMed:32322062).
CC {ECO:0000269|PubMed:32322062}.
CC -!- FUNCTION: [Processed sterol regulatory element-binding protein 2]: Key
CC transcription factor that regulates expression of genes involved in
CC cholesterol biosynthesis (PubMed:12177166, PubMed:32322062). Binds to
CC the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual
CC sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3')
CC and to SRE-1 (5'-ATCACCCCAC-3') (PubMed:7903453, PubMed:12177166).
CC Regulates transcription of genes related to cholesterol synthesis
CC pathway (PubMed:12177166, PubMed:32322062).
CC {ECO:0000269|PubMed:12177166, ECO:0000269|PubMed:32322062,
CC ECO:0000269|PubMed:7903453}.
CC -!- SUBUNIT: [Sterol regulatory element-binding protein 2]: Forms a tight
CC complex with SCAP, the SCAP-SREBP complex, in the endoplasmic reticulum
CC membrane (PubMed:19706601, PubMed:32322062). Interacts (via C-terminal
CC domain) with RNF139 (PubMed:19706601). {ECO:0000269|PubMed:19706601,
CC ECO:0000269|PubMed:32322062}.
CC -!- SUBUNIT: [Processed sterol regulatory element-binding protein 2]:
CC Homodimer; efficient DNA binding of the soluble transcription factor
CC fragment requires dimerization with another bHLH protein (By
CC similarity). Interacts with LMNA (By similarity).
CC {ECO:0000250|UniProtKB:Q3U1N2}.
CC -!- INTERACTION:
CC Q12772; Q92793: CREBBP; NbExp=2; IntAct=EBI-465059, EBI-81215;
CC Q12772; Q14192: FHL2; NbExp=3; IntAct=EBI-465059, EBI-701903;
CC Q12772; P41235: HNF4A; NbExp=2; IntAct=EBI-465059, EBI-1049011;
CC Q12772; Q96RN5: MED15; NbExp=2; IntAct=EBI-465059, EBI-394506;
CC Q12772; Q13952-2: NFYC; NbExp=3; IntAct=EBI-465059, EBI-11956831;
CC Q12772; P08047: SP1; NbExp=3; IntAct=EBI-465059, EBI-298336;
CC Q12772; P04637: TP53; NbExp=3; IntAct=EBI-465059, EBI-366083;
CC -!- SUBCELLULAR LOCATION: [Sterol regulatory element-binding protein 2]:
CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:12202038}; Multi-
CC pass membrane protein {ECO:0000255}. Golgi apparatus membrane
CC {ECO:0000303|PubMed:28849786}; Multi-pass membrane protein
CC {ECO:0000255}. Cytoplasmic vesicle, COPII-coated vesicle membrane
CC {ECO:0000303|PubMed:28849786}; Multi-pass membrane protein
CC {ECO:0000255}. Note=At high sterol concentrations, the SCAP-SREBP is
CC retained in the endoplasmic reticulum (PubMed:32322062). Low sterol
CC concentrations promote recruitment into COPII-coated vesicles and
CC transport of the SCAP-SREBP to the Golgi, where it is processed
CC (PubMed:32322062). {ECO:0000269|PubMed:32322062}.
CC -!- SUBCELLULAR LOCATION: [Processed sterol regulatory element-binding
CC protein 2]: Nucleus {ECO:0000269|PubMed:11477106,
CC ECO:0000269|PubMed:32322062}. Note=Transported into the nucleus with
CC the help of importin-beta. Dimerization of the bHLH domain is a
CC prerequisite for importin beta-dependent nuclear import.
CC {ECO:0000250|UniProtKB:Q3U1N2}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q12772-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q12772-2; Sequence=VSP_054283, VSP_054284, VSP_054285;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed in adult and fetal tissues.
CC {ECO:0000269|PubMed:7903453}.
CC -!- PTM: [Sterol regulatory element-binding protein 2]: Processed in the
CC Golgi apparatus, releasing the protein from the membrane
CC (PubMed:8626610, PubMed:32322062, PubMed:9651382, PubMed:10805775). At
CC low cholesterol the SCAP-SREBP complex is recruited into COPII vesicles
CC for export from the endoplasmic reticulum (PubMed:8626610,
CC PubMed:32322062, PubMed:9651382, PubMed:10805775). In the Golgi,
CC complex SREBPs are cleaved sequentially by site-1 (MBTPS1, S1P) and
CC site-2 (MBTPS2, S2P) protease (PubMed:8626610, PubMed:9651382,
CC PubMed:10805775, PubMed:32322062). The first cleavage by site-1
CC protease occurs within the luminal loop, the second cleavage by site-2
CC protease occurs within the first transmembrane domain, releasing the
CC transcription factor from the Golgi membrane (PubMed:9651382,
CC PubMed:10805775). Apoptosis triggers cleavage by the cysteine proteases
CC caspase-3 and caspase-7. Cleavage and activation is induced by mediated
CC cholesterol efflux (PubMed:8643593). {ECO:0000269|PubMed:10805775,
CC ECO:0000269|PubMed:32322062, ECO:0000269|PubMed:8626610,
CC ECO:0000269|PubMed:8643593, ECO:0000269|PubMed:9651382}.
CC -!- PTM: Phosphorylated by AMPK, leading to suppress protein processing and
CC nuclear translocation, and repress target gene expression.
CC {ECO:0000250|UniProtKB:Q3U1N2}.
CC -!- PTM: [Processed sterol regulatory element-binding protein 2]:
CC Ubiquitinated; the nuclear form has a rapid turnover and is rapidly
CC ubiquitinated and degraded by the proteasome in the nucleus.
CC {ECO:0000269|PubMed:11477106}.
CC -!- SIMILARITY: Belongs to the SREBP family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH51799.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; U02031; AAA50746.1; -; mRNA.
DR EMBL; CT841522; CAJ86452.1; -; mRNA.
DR EMBL; AL021453; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; Z99716; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC051385; AAH51385.1; -; mRNA.
DR EMBL; BC051799; AAH51799.1; ALT_INIT; mRNA.
DR EMBL; BC056158; AAH56158.1; -; mRNA.
DR CCDS; CCDS14023.1; -. [Q12772-1]
DR PIR; A49397; A54962.
DR RefSeq; NP_004590.2; NM_004599.3. [Q12772-1]
DR PDB; 1UKL; X-ray; 3.00 A; C/D/E/F=343-403.
DR PDBsum; 1UKL; -.
DR AlphaFoldDB; Q12772; -.
DR SMR; Q12772; -.
DR BioGRID; 112599; 324.
DR CORUM; Q12772; -.
DR DIP; DIP-263N; -.
DR ELM; Q12772; -.
DR IntAct; Q12772; 62.
DR MINT; Q12772; -.
DR STRING; 9606.ENSP00000354476; -.
DR BindingDB; Q12772; -.
DR ChEMBL; CHEMBL1795166; -.
DR CarbonylDB; Q12772; -.
DR GlyGen; Q12772; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; Q12772; -.
DR PhosphoSitePlus; Q12772; -.
DR BioMuta; SREBF2; -.
DR DMDM; 116242800; -.
DR EPD; Q12772; -.
DR jPOST; Q12772; -.
DR MassIVE; Q12772; -.
DR MaxQB; Q12772; -.
DR PaxDb; Q12772; -.
DR PeptideAtlas; Q12772; -.
DR PRIDE; Q12772; -.
DR ProteomicsDB; 58919; -. [Q12772-1]
DR Antibodypedia; 13093; 370 antibodies from 37 providers.
DR DNASU; 6721; -.
DR Ensembl; ENST00000361204.9; ENSP00000354476.4; ENSG00000198911.12. [Q12772-1]
DR GeneID; 6721; -.
DR KEGG; hsa:6721; -.
DR MANE-Select; ENST00000361204.9; ENSP00000354476.4; NM_004599.4; NP_004590.2.
DR UCSC; uc003bbi.5; human. [Q12772-1]
DR CTD; 6721; -.
DR DisGeNET; 6721; -.
DR GeneCards; SREBF2; -.
DR HGNC; HGNC:11290; SREBF2.
DR HPA; ENSG00000198911; Low tissue specificity.
DR MIM; 600481; gene.
DR neXtProt; NX_Q12772; -.
DR OpenTargets; ENSG00000198911; -.
DR PharmGKB; PA336; -.
DR VEuPathDB; HostDB:ENSG00000198911; -.
DR eggNOG; KOG2588; Eukaryota.
DR GeneTree; ENSGT00940000157339; -.
DR HOGENOM; CLU_008042_0_0_1; -.
DR InParanoid; Q12772; -.
DR OMA; VCRWWTS; -.
DR PhylomeDB; Q12772; -.
DR TreeFam; TF313894; -.
DR PathwayCommons; Q12772; -.
DR Reactome; R-HSA-1655829; Regulation of cholesterol biosynthesis by SREBP (SREBF).
DR Reactome; R-HSA-191273; Cholesterol biosynthesis.
DR Reactome; R-HSA-1989781; PPARA activates gene expression.
DR Reactome; R-HSA-2426168; Activation of gene expression by SREBF (SREBP).
DR Reactome; R-HSA-381340; Transcriptional regulation of white adipocyte differentiation.
DR Reactome; R-HSA-9619665; EGR2 and SOX10-mediated initiation of Schwann cell myelination.
DR SignaLink; Q12772; -.
DR SIGNOR; Q12772; -.
DR BioGRID-ORCS; 6721; 47 hits in 1104 CRISPR screens.
DR ChiTaRS; SREBF2; human.
DR EvolutionaryTrace; Q12772; -.
DR GeneWiki; SREBF2; -.
DR GenomeRNAi; 6721; -.
DR Pharos; Q12772; Tchem.
DR PRO; PR:Q12772; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; Q12772; protein.
DR Bgee; ENSG00000198911; Expressed in ganglionic eminence and 207 other tissues.
DR ExpressionAtlas; Q12772; baseline and differential.
DR Genevisible; Q12772; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0012507; C:ER to Golgi transport vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:UniProtKB.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0070888; F:E-box binding; IDA:BHF-UCL.
DR GO; GO:0008022; F:protein C-terminus binding; IPI:UniProtKB.
DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0071499; P:cellular response to laminar fluid shear stress; NAS:BHF-UCL.
DR GO; GO:0071404; P:cellular response to low-density lipoprotein particle stimulus; IEP:BHF-UCL.
DR GO; GO:0009267; P:cellular response to starvation; IMP:ParkinsonsUK-UCL.
DR GO; GO:0042632; P:cholesterol homeostasis; IEA:Ensembl.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0006629; P:lipid metabolic process; TAS:ProtInc.
DR GO; GO:0090370; P:negative regulation of cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045542; P:positive regulation of cholesterol biosynthetic process; IDA:UniProtKB.
DR GO; GO:0010886; P:positive regulation of cholesterol storage; IDA:BHF-UCL.
DR GO; GO:1902895; P:positive regulation of miRNA transcription; IEA:Ensembl.
DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; HMP:ParkinsonsUK-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; HMP:ParkinsonsUK-UCL.
DR GO; GO:0008593; P:regulation of Notch signaling pathway; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0032933; P:SREBP signaling pathway; IDA:UniProtKB.
DR Gene3D; 4.10.280.10; -; 1.
DR IDEAL; IID00242; -.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR Pfam; PF00010; HLH; 1.
DR SMART; SM00353; HLH; 1.
DR SUPFAM; SSF47459; SSF47459; 1.
DR PROSITE; PS50888; BHLH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Cholesterol metabolism;
KW Cytoplasmic vesicle; Direct protein sequencing; DNA-binding;
KW Endoplasmic reticulum; Golgi apparatus; Isopeptide bond; Lipid metabolism;
KW Membrane; Nucleus; Phosphoprotein; Reference proteome; Steroid metabolism;
KW Sterol metabolism; Transcription; Transcription regulation; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..1141
FT /note="Sterol regulatory element-binding protein 2"
FT /id="PRO_0000127452"
FT CHAIN 1..484
FT /note="Processed sterol regulatory element-binding protein
FT 2"
FT /evidence="ECO:0000305|PubMed:10805775,
FT ECO:0000305|PubMed:9651382"
FT /id="PRO_0000314033"
FT TOPO_DOM 1..479
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 480..500
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 501..533
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 534..554
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 555..1139
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 330..380
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT REGION 1..50
FT /note="Transcriptional activation (acidic)"
FT /evidence="ECO:0000250|UniProtKB:P36956"
FT REGION 48..144
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 237..491
FT /note="Interaction with LMNA"
FT /evidence="ECO:0000250|UniProtKB:Q3U1N2"
FT REGION 380..401
FT /note="Leucine-zipper"
FT COMPBIAS 50..127
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 468..469
FT /note="Cleavage; by caspase-3 and caspase-7"
FT /evidence="ECO:0000269|PubMed:8643593"
FT SITE 484..485
FT /note="Cleavage; by MBTPS2"
FT /evidence="ECO:0000269|PubMed:10805775,
FT ECO:0000269|PubMed:9651382"
FT SITE 522..523
FT /note="Cleavage; by MBTPS1"
FT /evidence="ECO:0000269|PubMed:10805775"
FT MOD_RES 855
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1098
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 464
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT VAR_SEQ 273..275
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054283"
FT VAR_SEQ 589..684
FT /note="DFAAAAGNLQTCLAVLGRALPTSRLDLACSLSWNVIRYSLQKLRLVRWLLKK
FT VFQCRRATPATEAGFEDEAKTSARDAALAYHRLHQLHITGKLPA -> VYGKKSGATHS
FT IEEELNIHISRGTRTRTLLSSRRFCSCCRQPTNLPGSFGPGTAHLPPGPGLQPLLERDP
FT LQPAEATPGALAAQESLPVPAGHASH (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054284"
FT VAR_SEQ 685..1141
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054285"
FT VARIANT 273
FT /note="A -> S (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036394"
FT VARIANT 347
FT /note="N -> K (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036395"
FT VARIANT 536
FT /note="M -> L (in dbSNP:rs17002714)"
FT /id="VAR_049550"
FT VARIANT 595
FT /note="G -> A (in dbSNP:rs2228314)"
FT /evidence="ECO:0000269|PubMed:7903453"
FT /id="VAR_028440"
FT VARIANT 623
FT /note="V -> M (in dbSNP:rs2229440)"
FT /id="VAR_028441"
FT VARIANT 860
FT /note="R -> S (in dbSNP:rs2228313)"
FT /id="VAR_049551"
FT MUTAGEN 342
FT /note="Y->R: Abolished transactivation activity."
FT /evidence="ECO:0000269|PubMed:12177166"
FT MUTAGEN 478..481
FT /note="DRSR->AAAA: Loss of cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:8626610,
FT ECO:0000269|PubMed:9651382"
FT MUTAGEN 478..481
FT /note="DRSR->AS: Loss of cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:8626610,
FT ECO:0000269|PubMed:9651382"
FT MUTAGEN 478
FT /note="D->A: No effect on proteolytic processing in
FT response to low sterol."
FT /evidence="ECO:0000269|PubMed:8626610"
FT MUTAGEN 479..481
FT /note="RSR->AAA: Loss of cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:9651382"
FT MUTAGEN 479
FT /note="R->A: No effect on cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:9651382"
FT MUTAGEN 481
FT /note="R->A: No effect on cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:9651382"
FT MUTAGEN 484..485
FT /note="LC->FF: No effect on cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:9651382"
FT MUTAGEN 484
FT /note="L->A: No effect on cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:9651382"
FT MUTAGEN 485
FT /note="C->A: No effect on cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:9651382"
FT MUTAGEN 490..491
FT /note="LC->NP: Restores cleavage by S2P; when associated
FT with F-495 and L-496. No effect on site of cleavage by
FT S2P."
FT /evidence="ECO:0000269|PubMed:10805775"
FT MUTAGEN 495..496
FT /note="NP->FL: Loss of cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:10805775"
FT MUTAGEN 495
FT /note="N->F: Reduced cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:10805775"
FT MUTAGEN 496
FT /note="P->L: Reduced cleavage by S2P."
FT /evidence="ECO:0000269|PubMed:10805775"
FT MUTAGEN 519
FT /note="R->A: Loss of proteolytic processing in response to
FT low sterol."
FT /evidence="ECO:0000269|PubMed:8626610"
FT MUTAGEN 519
FT /note="R->K: No effect on proteolytic processing in
FT response to low sterol."
FT /evidence="ECO:0000269|PubMed:8626610"
FT CONFLICT 961
FT /note="A -> G (in Ref. 1; AAA50746)"
FT /evidence="ECO:0000305"
FT CONFLICT 1045
FT /note="A -> G (in Ref. 1; AAA50746)"
FT /evidence="ECO:0000305"
FT HELIX 346..357
FT /evidence="ECO:0007829|PDB:1UKL"
FT TURN 366..368
FT /evidence="ECO:0007829|PDB:1UKL"
FT HELIX 369..399
FT /evidence="ECO:0007829|PDB:1UKL"
SQ SEQUENCE 1141 AA; 123688 MW; 481B1D8E2A2306D2 CRC64;
MDDSGELGGL ETMETLTELG DELTLGDIDE MLQFVSNQVG EFPDLFSEQL CSSFPGSGGS
GSSSGSSGSS SSSSNGRGSS SGAVDPSVQR SFTQVTLPSF SPSAASPQAP TLQVKVSPTS
VPTTPRATPI LQPRPQPQPQ PQTQLQQQTV MITPTFSTTP QTRIIQQPLI YQNAATSFQV
LQPQVQSLVT SSQVQPVTIQ QQVQTVQAQR VLTQTANGTL QTLAPATVQT VAAPQVQQVP
VLVQPQIIKT DSLVLTTLKT DGSPVMAAVQ NPALTALTTP IQTAALQVPT LVGSSGTILT
TMPVMMGQEK VPIKQVPGGV KQLEPPKEGE RRTTHNIIEK RYRSSINDKI IELKDLVMGT
DAKMHKSGVL RKAIDYIKYL QQVNHKLRQE NMVLKLANQK NKLLKGIDLG SLVDNEVDLK
IEDFNQNVLL MSPPASDSGS QAGFSPYSID SEPGSPLLDD AKVKDEPDSP PVALGMVDRS
RILLCVLTFL CLSFNPLTSL LQWGGAHDSD QHPHSGSGRS VLSFESGSGG WFDWMMPTLL
LWLVNGVIVL SVFVKLLVHG EPVIRPHSRS SVTFWRHRKQ ADLDLARGDF AAAAGNLQTC
LAVLGRALPT SRLDLACSLS WNVIRYSLQK LRLVRWLLKK VFQCRRATPA TEAGFEDEAK
TSARDAALAY HRLHQLHITG KLPAGSACSD VHMALCAVNL AECAEEKIPP STLVEIHLTA
AMGLKTRCGG KLGFLASYFL SRAQSLCGPE HSAVPDSLRW LCHPLGQKFF MERSWSVKSA
AKESLYCAQR NPADPIAQVH QAFCKNLLER AIESLVKPQA KKKAGDQEEE SCEFSSALEY
LKLLHSFVDS VGVMSPPLSR SSVLKSALGP DIICRWWTSA ITVAISWLQG DDAAVRSHFT
KVERIPKALE VTESPLVKAI FHACRAMHAS LPGKADGQQS SFCHCERASG HLWSSLNVSG
ATSDPALNHV VQLLTCDLLL SLRTALWQKQ ASASQAVGET YHASGAELAG FQRDLGSLRR
LAHSFRPAYR KVFLHEATVR LMAGASPTRT HQLLEHSLRR RTTQSTKHGE VDAWPGQRER
ATAILLACRH LPLSFLSSPG QRAVLLAEAA RTLEKVGDRR SCNDCQQMIV KLGGGTAIAA
S
