ID SRBP2_HUMAN Reviewed; 1141 AA. AC Q12772; Q6GTH7; Q86V36; Q9UH04; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 2. DT 13-JUL-2010, entry version 107. DE RecName: Full=Sterol regulatory element-binding protein 2; DE Short=SREBP-2; DE AltName: Full=Sterol regulatory element-binding transcription factor 2; DE AltName: Full=Class D basic helix-loop-helix protein 2; DE Short=bHLHd2; DE Contains: DE RecName: Full=Processed sterol regulatory element-binding protein 2; GN Name=SREBF2; Synonyms=BHLHD2, SREBP2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ALA-595. RX MEDLINE=94089681; 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]. 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 MEDLINE=20057165; PubMed=10591208; DOI=10.1038/990031; RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J., RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G., RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R., RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E., RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G., RA 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., RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A., RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M., RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T., RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J., RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T., RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T., RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L., RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M., RA 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., RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T., RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I., RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H., RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L., RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z., RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P., RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S., RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J., RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T., RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J., RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R., RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P., RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E., RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X., RA Khan A.S., Lane L., Tilahun Y., Wright H.; RT "The DNA sequence of human chromosome 22."; RL Nature 402:489-495(1999). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP PROTEIN SEQUENCE OF 91-109. RX MEDLINE=94006541; PubMed=8402897; DOI=10.1016/0092-8674(93)90690-R; RA Yokoyama C., Wang X., Briggs M.R., Admon A., Wu J., Hua X., RA Goldstein J.L., Brown M.S.; RT "SREBP-1, a basic-helix-loop-helix-leucine zipper protein that RT controls transcription of the low density lipoprotein receptor gene."; RL Cell 75:187-197(1993). RN [6] RP CHARACTERIZATION, AND MUTAGENESIS OF ASP-478; ARG-519 AND RP 478-ASP--ARG-481. RX MEDLINE=96215341; 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 RT requires sequences on both sides of the endoplasmic reticulum RT membrane."; RL J. Biol. Chem. 271:10379-10384(1996). RN [7] RP CLEAVAGE AT ASP-468 BY CASPASES. RX MEDLINE=96224303; 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 [8] RP CLEAVAGE BY S2P, AND MUTAGENESIS OF ARG-479; ARG-481; LEU-484; RP CYS-485; 478-ASP--ARG-481; 479-ARG--ARG-481 AND 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 RT occurs at transmembrane junction as determined by cysteine panning."; RL J. Biol. Chem. 273:17801-17809(1998). RN [9] RP CLEAVAGE BY S2P, AND MUTAGENESIS OF ASN-495; PRO-496; 490-LEU-CYS-491 RP AND 495-ASN-PRO-496. RX MEDLINE=20266329; 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 [10] 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., RA Imamoto N., Yoshimura M., Sakai H., Chong K.T., Tsukihara T., RA 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 [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-840, AND MASS RP SPECTROMETRY. RC TISSUE=Embryonic kidney; RX PubMed=17287340; DOI=10.1073/pnas.0611217104; RA Molina H., Horn D.M., Tang N., Mathivanan S., Pandey A.; RT "Global proteomic profiling of phosphopeptides using electron transfer RT dissociation tandem mass spectrometry."; RL Proc. Natl. Acad. Sci. U.S.A. 104:2199-2204(2007). RN [12] 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., RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C., RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., RA Vogelstein B., Kinzler K.W., Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal RT cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Transcriptional activator required for lipid CC homeostasis. Regulates transcription of the LDL receptor gene as CC well as the cholesterol and to a lesser degree the fatty acid CC synthesis pathway (By similarity). Binds the sterol regulatory CC element 1 (SRE-1) (5'-ATCACCCCAC-3') found in the flanking region CC of the LDRL and HMG-CoA synthase genes. CC -!- SUBUNIT: Forms a tight complex with SCAP in the ER membrane. CC Efficient DNA binding of the soluble transcription factor fragment CC requires dimerization with another bHLH protein. Interacts with CC LMNA. CC -!- INTERACTION: CC P84022:SMAD3; NbExp=1; IntAct=EBI-465059, EBI-347161; CC P08047:SP1; NbExp=1; IntAct=EBI-465059, EBI-298336; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass CC membrane protein. Golgi apparatus membrane; Multi-pass membrane CC protein. Cytoplasmic vesicle, COPII-coated vesicle membrane; CC Multi-pass membrane protein. Note=Moves from the endoplasmic CC reticulum to the Golgi in the absence of sterols. CC -!- SUBCELLULAR LOCATION: Processed sterol regulatory element-binding CC protein 2: Nucleus. CC -!- TISSUE SPECIFICITY: Ubiquitously expressed in adult and fetal CC tissues. CC -!- PTM: At low cholesterol the SCAP/SREBP complex is recruited into CC COPII vesicles for export from the ER. In the Golgi complex SREBPs CC are cleaved sequentially by site-1 and site-2 protease. The first CC cleavage by site-1 protease occurs within the luminal loop, the CC second cleavage by site-2 protease occurs within the first CC transmembrane domain and releases the transcription factor from CC the Golgi membrane. Apoptosis triggers cleavage by the cysteine CC proteases caspase-3 and caspase-7. CC -!- SIMILARITY: Belongs to the SREBP family. CC -!- SIMILARITY: Contains 1 basic helix-loop-helix (bHLH) domain. CC -!- SEQUENCE CAUTION: CC Sequence=AAH51799.1; Type=Erroneous initiation; 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; U02031; AAA50746.1; -; mRNA. DR EMBL; CT841522; CAJ86452.1; -; mRNA. DR EMBL; AL021453; CAI22917.1; -; Genomic_DNA. DR EMBL; Z99716; CAI22917.1; JOINED; Genomic_DNA. DR EMBL; Z99716; CAI41688.1; -; Genomic_DNA. DR EMBL; AL021453; CAI41688.1; JOINED; Genomic_DNA. DR EMBL; BC051799; AAH51799.1; ALT_INIT; mRNA. DR EMBL; BC056158; AAH56158.1; -; mRNA. DR IPI; IPI00328793; -. DR PIR; A49397; A54962. DR RefSeq; NP_004590.2; -. DR UniGene; Hs.443258; -. DR PDB; 1UKL; X-ray; 3.00 A; C/D/E/F=343-403. DR PDBsum; 1UKL; -. DR DIP; DIP-263N; -. DR IntAct; Q12772; 10. DR MINT; MINT-144301; -. DR STRING; Q12772; -. DR PhosphoSite; Q12772; -. DR PRIDE; Q12772; -. DR Ensembl; ENST00000361204; ENSP00000354476; ENSG00000198911; Homo sapiens. DR GeneID; 6721; -. DR KEGG; hsa:6721; -. DR UCSC; uc003bbi.1; human. DR CTD; 6721; -. DR GeneCards; GC22P040553; -. DR H-InvDB; HIX0016533; -. DR HGNC; HGNC:11290; SREBF2. DR HPA; HPA031962; -. DR MIM; 600481; gene. DR Orphanet; 406; Familial hypercholesterolemia. DR PharmGKB; PA336; -. DR eggNOG; prNOG15145; -. DR HOGENOM; HBG356914; -. DR HOVERGEN; HBG061592; -. DR InParanoid; Q12772; -. DR OMA; RKVFLHE; -. DR OrthoDB; EOG9QJV6D; -. DR NextBio; 26218; -. DR PMAP-CutDB; Q12772; -. DR ArrayExpress; Q12772; -. DR Bgee; Q12772; -. DR CleanEx; HS_SREBF2; -. DR Genevestigator; Q12772; -. DR GO; GO:0012507; C:ER to Golgi transport vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; IDA:UniProtKB. DR GO; GO:0008022; F:protein C-terminus binding; IPI:UniProtKB. DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW. DR GO; GO:0006350; P:transcription; IEA:UniProtKB-KW. DR InterPro; IPR011598; HLH_DNA-bd. DR InterPro; IPR001092; HLH_DNA-bd_dom. DR Gene3D; G3DSA:4.10.280.10; HLH_DNA_bd; 1. DR Pfam; PF00010; HLH; 1. DR SMART; SM00353; HLH; 1. DR SUPFAM; SSF47459; HLH_basic; 1. DR PROSITE; PS50888; HLH; 1. PE 1: Evidence at protein level; KW 3D-structure; Activator; Cholesterol metabolism; Complete proteome; KW Cytoplasmic vesicle; Direct protein sequencing; DNA-binding; KW Endoplasmic reticulum; Golgi apparatus; Lipid metabolism; Membrane; KW Nucleus; Phosphoprotein; Polymorphism; Steroid metabolism; KW Transcription; Transcription regulation; Transmembrane. FT CHAIN 1 1141 Sterol regulatory element-binding protein FT 2. FT /FTId=PRO_0000127452. FT CHAIN 1 484 Processed sterol regulatory element- FT binding protein 2. FT /FTId=PRO_0000314033. FT TOPO_DOM 1 479 Cytoplasmic (Potential). FT TRANSMEM 480 500 Helical; (Potential). FT TOPO_DOM 501 533 Lumenal (Potential). FT TRANSMEM 534 554 Helical; (Potential). FT TOPO_DOM 555 1139 Cytoplasmic (Potential). FT DOMAIN 344 381 Helix-loop-helix motif. FT DOMAIN 380 401 Leucine-zipper. FT DNA_BIND 330 343 Basic motif. FT REGION 1 50 Transcriptional activation (acidic). FT REGION 237 491 Interaction with LMNA (By similarity). FT COMPBIAS 52 124 Gly/Pro/Ser-rich. FT COMPBIAS 125 244 Gln-rich. FT SITE 468 469 Cleavage; by caspase-3 and caspase-7. FT SITE 484 485 Cleavage; by S2P. FT SITE 522 523 Cleavage; by S1P. FT MOD_RES 840 840 Phosphotyrosine. FT MOD_RES 1121 1121 Phosphoserine (By similarity). FT VARIANT 273 273 A -> S (in a breast cancer sample; FT somatic mutation). FT /FTId=VAR_036394. FT VARIANT 347 347 N -> K (in a breast cancer sample; FT somatic mutation). FT /FTId=VAR_036395. FT VARIANT 536 536 M -> L (in dbSNP:rs17002714). FT /FTId=VAR_049550. FT VARIANT 595 595 G -> A (in dbSNP:rs2228314). FT /FTId=VAR_028440. FT VARIANT 623 623 V -> M (in dbSNP:rs2229440). FT /FTId=VAR_028441. FT VARIANT 860 860 R -> S (in dbSNP:rs2228313). FT /FTId=VAR_049551. FT MUTAGEN 478 481 DRSR->AAAA: Loss of cleavage by S2P. FT MUTAGEN 478 481 DRSR->AS: Loss of cleavage by S2P. FT MUTAGEN 478 478 D->A: No effect on proteolytic processing FT in response to low sterol. FT MUTAGEN 479 481 RSR->AAA: Loss of cleavage by S2P. FT MUTAGEN 479 479 R->A: No effect on cleavage by S2P. FT MUTAGEN 481 481 R->A: No effect on cleavage by S2P. FT MUTAGEN 484 485 LC->FF: No effect on cleavage by S2P. FT MUTAGEN 484 484 L->A: No effect on cleavage by S2P. FT MUTAGEN 485 485 C->A: No effect on cleavage by S2P. FT MUTAGEN 490 491 LC->NP: Restores cleavage by S2P; when FT associated with F-495 and L-496. No FT effect on site of cleavage by S2P. FT MUTAGEN 495 496 NP->FL: Loss of cleavage by S2P. FT MUTAGEN 495 495 N->F: Reduced cleavage by S2P. FT MUTAGEN 496 496 P->L: Reduced cleavage by S2P. FT MUTAGEN 519 519 R->A: Loss of proteolytic processing in FT response to low sterol. FT MUTAGEN 519 519 R->K: No effect on proteolytic processing FT in response to low sterol. FT CONFLICT 961 961 A -> G (in Ref. 1; AAA50746). FT CONFLICT 1045 1045 A -> G (in Ref. 1; AAA50746). FT HELIX 346 357 FT TURN 366 368 FT HELIX 369 399 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 //