Full text data of SREBF2
SREBF2
(BHLHD2, SREBP2)
[Confidence: low (only semi-automatic identification from reviews)]
Sterol regulatory element-binding protein 2; SREBP-2 (Class D basic helix-loop-helix protein 2; bHLHd2; Sterol regulatory element-binding transcription factor 2; Processed sterol regulatory element-binding protein 2)
Sterol regulatory element-binding protein 2; SREBP-2 (Class D basic helix-loop-helix protein 2; bHLHd2; Sterol regulatory element-binding transcription factor 2; Processed sterol regulatory element-binding protein 2)
UniProt
Q12772
ID SRBP2_HUMAN Reviewed; 1141 AA.
AC Q12772; Q6GTH7; Q86V36; Q9UH04;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 17-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Sterol regulatory element-binding protein 2;
DE Short=SREBP-2;
DE AltName: Full=Class D basic helix-loop-helix protein 2;
DE Short=bHLHd2;
DE AltName: Full=Sterol regulatory element-binding transcription factor 2;
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 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 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 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 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 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 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 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
RT protein-2 (SREBP-2)/SREBP cleavage-activated protein and reduces
RT SREBP-2 cleavage.";
RL J. Biol. Chem. 284:28995-29004(2009).
RN [11]
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 [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. Component of SCAP/SREBP complex composed of SREBF2, SCAP and
CC RNF139; the complex hampers the interaction between SCAP and
CC SEC24B, thereby reducing SREBF2 proteolytic processing. Interacts
CC (via C-terminus domain) with RNF139.
CC -!- INTERACTION:
CC P08047:SP1; NbExp=3; IntAct=EBI-465059, EBI-298336;
CC P04637:TP53; NbExp=3; IntAct=EBI-465059, EBI-366083;
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 -!- PTM: Phosphorylated by AMPK, leading to suppress protein
CC processing and nuclear translocation, and repress target gene
CC expression (By similarity).
CC -!- SIMILARITY: Belongs to the SREBP family.
CC -!- SIMILARITY: Contains 1 bHLH (basic helix-loop-helix) domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH51799.1; Type=Erroneous initiation;
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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 PIR; A49397; A54962.
DR RefSeq; NP_004590.2; NM_004599.3.
DR UniGene; Hs.443258; -.
DR PDB; 1UKL; X-ray; 3.00 A; C/D/E/F=343-403.
DR PDBsum; 1UKL; -.
DR ProteinModelPortal; Q12772; -.
DR SMR; Q12772; 343-403.
DR DIP; DIP-263N; -.
DR IntAct; Q12772; 44.
DR MINT; MINT-144301; -.
DR STRING; 9606.ENSP00000354476; -.
DR BindingDB; Q12772; -.
DR ChEMBL; CHEMBL1795166; -.
DR PhosphoSite; Q12772; -.
DR DMDM; 116242800; -.
DR PaxDb; Q12772; -.
DR PRIDE; Q12772; -.
DR DNASU; 6721; -.
DR Ensembl; ENST00000361204; ENSP00000354476; ENSG00000198911.
DR GeneID; 6721; -.
DR KEGG; hsa:6721; -.
DR UCSC; uc003bbi.3; human.
DR CTD; 6721; -.
DR GeneCards; GC22P042273; -.
DR HGNC; HGNC:11290; SREBF2.
DR HPA; HPA031962; -.
DR MIM; 600481; gene.
DR neXtProt; NX_Q12772; -.
DR PharmGKB; PA336; -.
DR eggNOG; NOG242942; -.
DR HOGENOM; HOG000007091; -.
DR HOVERGEN; HBG061592; -.
DR InParanoid; Q12772; -.
DR KO; K09107; -.
DR OMA; DVICRWW; -.
DR OrthoDB; EOG7D85VS; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_147768; SREBP2 (SREBF2) is retained in the endoplasmic reticulum by SCAP:INSIG2:oxysterol.
DR Reactome; REACT_147840; SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:cholesterol:INSIG.
DR Reactome; REACT_147890; SREBP2:SCAP Binds CopII Coat Complex.
DR Reactome; REACT_147893; SREBP2:SCAP Transits to the Golgi.
DR EvolutionaryTrace; Q12772; -.
DR GeneWiki; SREBF2; -.
DR GenomeRNAi; 6721; -.
DR NextBio; 26218; -.
DR PMAP-CutDB; Q12772; -.
DR PRO; PR:Q12772; -.
DR ArrayExpress; Q12772; -.
DR Bgee; Q12772; -.
DR CleanEx; HS_SREBF2; -.
DR Genevestigator; Q12772; -.
DR GO; GO:0005829; C:cytosol; 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:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; IDA:UniProtKB.
DR GO; GO:0070888; F:E-box binding; IDA:BHF-UCL.
DR GO; GO:0000978; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; IEA:Ensembl.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0071499; P:cellular response to laminar fluid shear stress; NAS:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0090370; P:negative regulation of cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0010886; P:positive regulation of cholesterol storage; IDA:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:2000188; P:regulation of cholesterol homeostasis; IEA:Ensembl.
DR GO; GO:0072368; P:regulation of lipid transport by negative regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0055098; P:response to low-density lipoprotein particle stimulus; IEP:BHF-UCL.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
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; Cholesterol metabolism; Complete proteome;
KW Cytoplasmic vesicle; Direct protein sequencing; DNA-binding;
KW Endoplasmic reticulum; Golgi apparatus; Lipid metabolism; Membrane;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Steroid metabolism; Sterol metabolism; Transcription;
KW Transcription regulation; Transmembrane; Transmembrane helix.
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 330 380 bHLH.
FT REGION 1 50 Transcriptional activation (acidic).
FT REGION 237 491 Interaction with LMNA (By similarity).
FT REGION 380 401 Leucine-zipper.
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 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
//
ID SRBP2_HUMAN Reviewed; 1141 AA.
AC Q12772; Q6GTH7; Q86V36; Q9UH04;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 17-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Sterol regulatory element-binding protein 2;
DE Short=SREBP-2;
DE AltName: Full=Class D basic helix-loop-helix protein 2;
DE Short=bHLHd2;
DE AltName: Full=Sterol regulatory element-binding transcription factor 2;
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 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 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 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 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 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 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 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
RT protein-2 (SREBP-2)/SREBP cleavage-activated protein and reduces
RT SREBP-2 cleavage.";
RL J. Biol. Chem. 284:28995-29004(2009).
RN [11]
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 [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. Component of SCAP/SREBP complex composed of SREBF2, SCAP and
CC RNF139; the complex hampers the interaction between SCAP and
CC SEC24B, thereby reducing SREBF2 proteolytic processing. Interacts
CC (via C-terminus domain) with RNF139.
CC -!- INTERACTION:
CC P08047:SP1; NbExp=3; IntAct=EBI-465059, EBI-298336;
CC P04637:TP53; NbExp=3; IntAct=EBI-465059, EBI-366083;
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 -!- PTM: Phosphorylated by AMPK, leading to suppress protein
CC processing and nuclear translocation, and repress target gene
CC expression (By similarity).
CC -!- SIMILARITY: Belongs to the SREBP family.
CC -!- SIMILARITY: Contains 1 bHLH (basic helix-loop-helix) domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH51799.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
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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 PIR; A49397; A54962.
DR RefSeq; NP_004590.2; NM_004599.3.
DR UniGene; Hs.443258; -.
DR PDB; 1UKL; X-ray; 3.00 A; C/D/E/F=343-403.
DR PDBsum; 1UKL; -.
DR ProteinModelPortal; Q12772; -.
DR SMR; Q12772; 343-403.
DR DIP; DIP-263N; -.
DR IntAct; Q12772; 44.
DR MINT; MINT-144301; -.
DR STRING; 9606.ENSP00000354476; -.
DR BindingDB; Q12772; -.
DR ChEMBL; CHEMBL1795166; -.
DR PhosphoSite; Q12772; -.
DR DMDM; 116242800; -.
DR PaxDb; Q12772; -.
DR PRIDE; Q12772; -.
DR DNASU; 6721; -.
DR Ensembl; ENST00000361204; ENSP00000354476; ENSG00000198911.
DR GeneID; 6721; -.
DR KEGG; hsa:6721; -.
DR UCSC; uc003bbi.3; human.
DR CTD; 6721; -.
DR GeneCards; GC22P042273; -.
DR HGNC; HGNC:11290; SREBF2.
DR HPA; HPA031962; -.
DR MIM; 600481; gene.
DR neXtProt; NX_Q12772; -.
DR PharmGKB; PA336; -.
DR eggNOG; NOG242942; -.
DR HOGENOM; HOG000007091; -.
DR HOVERGEN; HBG061592; -.
DR InParanoid; Q12772; -.
DR KO; K09107; -.
DR OMA; DVICRWW; -.
DR OrthoDB; EOG7D85VS; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_147768; SREBP2 (SREBF2) is retained in the endoplasmic reticulum by SCAP:INSIG2:oxysterol.
DR Reactome; REACT_147840; SREBP1A/1C/2 is retained in the endoplasmic reticulum by SCAP:cholesterol:INSIG.
DR Reactome; REACT_147890; SREBP2:SCAP Binds CopII Coat Complex.
DR Reactome; REACT_147893; SREBP2:SCAP Transits to the Golgi.
DR EvolutionaryTrace; Q12772; -.
DR GeneWiki; SREBF2; -.
DR GenomeRNAi; 6721; -.
DR NextBio; 26218; -.
DR PMAP-CutDB; Q12772; -.
DR PRO; PR:Q12772; -.
DR ArrayExpress; Q12772; -.
DR Bgee; Q12772; -.
DR CleanEx; HS_SREBF2; -.
DR Genevestigator; Q12772; -.
DR GO; GO:0005829; C:cytosol; 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:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; IDA:UniProtKB.
DR GO; GO:0070888; F:E-box binding; IDA:BHF-UCL.
DR GO; GO:0000978; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; IEA:Ensembl.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0071499; P:cellular response to laminar fluid shear stress; NAS:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0090370; P:negative regulation of cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0010886; P:positive regulation of cholesterol storage; IDA:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:2000188; P:regulation of cholesterol homeostasis; IEA:Ensembl.
DR GO; GO:0072368; P:regulation of lipid transport by negative regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0055098; P:response to low-density lipoprotein particle stimulus; IEP:BHF-UCL.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
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; Cholesterol metabolism; Complete proteome;
KW Cytoplasmic vesicle; Direct protein sequencing; DNA-binding;
KW Endoplasmic reticulum; Golgi apparatus; Lipid metabolism; Membrane;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Steroid metabolism; Sterol metabolism; Transcription;
KW Transcription regulation; Transmembrane; Transmembrane helix.
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 330 380 bHLH.
FT REGION 1 50 Transcriptional activation (acidic).
FT REGION 237 491 Interaction with LMNA (By similarity).
FT REGION 380 401 Leucine-zipper.
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 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
//
MIM
600481
*RECORD*
*FIELD* NO
600481
*FIELD* TI
*600481 STEROL REGULATORY ELEMENT-BINDING TRANSCRIPTION FACTOR 2; SREBF2
;;STEROL REGULATORY ELEMENT-BINDING PROTEIN 2; SREBP2
read more*FIELD* TX
DESCRIPTION
The sterol regulatory element (SRE)-binding protein-2 (SREBP2) is
structurally related to SREBP1 (SREBF1; 184756), and both control
cholesterol homeostasis by stimulating transcription of sterol-regulated
genes (summary by Osborne, 2001).
CLONING
Hua et al. (1993) cloned SREBF2 from a HeLa cell cDNA library. The
deduced 1,141-amino acid protein has a calculated molecular mass of 124
kD. SREBF2 has an acidic N-terminal domain, a basic helix-loop-helix
leucine zipper (bHLH-ZIP) motif, and a long C terminus. It also has
histidine, glutamic acid, and arginine residues implicated in DNA
recognition by other bHLH-ZIP proteins. SREBF2 and SREBF1 share 47%
amino acid identity overall and 71% identity in the bHLH-ZIP region.
Northern blot analysis revealed a major SREBF2 transcript of 5.2 kb in
all tissues examined. A minor transcript of about 4.2 kb was also
observed.
Miserez et al. (1997) found that SREBP2 was expressed ubiquitously as 2
mRNAs (4.2 and 5.2 kb) that differ in their 3-prime untranslated regions
because of different polyadenylation signals.
GENE STRUCTURE
Miserez et al. (1997) found that the SREBF2 gene contains 19 exons and
spans 72 kb, with a sterol regulatory element in the promoter region.
MAPPING
Hua et al. (1995) isolated a genomic cosmid clone for SREBF2 and mapped
the gene to 22q13 by analysis of human/rodent somatic cell hybrids and
fluorescence in situ hybridization.
GENE FUNCTION
By transfection of human 293 cells, Hua et al. (1993) found that SREBF2,
like SREBF1, drove transcription from a reporter gene containing SRE1 in
both the presence or absence of sterols.
Cholesterol homeostasis in animal cells is achieved by regulated
cleavage of SREBPs, membrane-bound transcription factors. Proteolytic
release of the active domains of SREBPs from membranes requires a
sterol-sensing protein called SCAP (601510), which forms a complex with
SREBPs. In sterol-depleted cells, DeBose-Boyd et al. (1999) found that
SCAP escorts SREBPs from the endoplasmic reticulum (ER) to the Golgi,
where SREBPs are cleaved by site-1 protease (S1P; 603355). The authors
showed that sterols block this transport and abolish cleavage.
Relocating active S1P from Golgi to ER by treating cells with brefeldin
A or by fusing the ER retention signal KDEL to S1P obviated the SCAP
requirement and rendered cleavage insensitive to sterols. DeBose-Boyd et
al. (1999) concluded that transport-dependent proteolysis may be a
common mechanism to regulate the processing of membrane proteins.
Shimano et al. (1997) concluded that SREBP2 can replace SREBP1 in
regulating cholesterol synthesis in livers of mice and that the higher
potency of SREBP2 leads to excessive hepatic cholesterol synthesis in
these animals.
See review by Osborne (2001).
Najafi-Shoushtari et al. (2010) and Rayner et al. (2010) found that the
microRNA miR33 (612156) embedded within intron 16 of the SREBP2 gene
plays a role in control of cholesterol homeostasis through
posttranscriptional repression of the adenosine triphosphate-binding
cassette transporter A1 (ABCA1; 600046).
Jeon et al. (2008) found that the nuclear level of hepatic Srebp2 was
elevated in mice fed a diet supplemented with lovastatin and ezetimibe
(L/E) to limit dietary sterol absorption and reduce HMG-CoA reductase
(HMGCR; 142910) activity. Genomic promoter-wide ChIP-chip analysis
revealed that Srebp2 bound a number of promoters for genes encoding
bitter taste-responding type-2 taste receptors (T2Rs; see 604867), which
are expressed in gut enteroendocrine cells and in the tongue and oral
cavity. Sterol depletion in the mouse enteroendocrine cell line STC-1,
or expression of human SREBP2 in STC-1 cells, led to increased T2R
expression. T2R expression was also increased in the proximal small
intestine of L/E-treated mice. In contrast, T2R expression in the tongue
was not induced by L/E feeding. Jeon et al. (2008) proposed that a low
cholesterol diet may induce SREBP2-mediated activation of bitter
signaling in the gut to prevent absorption of potentially toxic bitter
substances in plant-derived foods, in addition to maximizing lipid
uptake.
BIOCHEMICAL FEATURES
- Crystal Structure
Lee et al. (2003) showed the crystal structure of importin-beta (see
602738) complexed with the active form of SREBP2. Importin-beta uses
characteristic long helices like a pair of chopsticks to interact with
an SREBP2 dimer. Importin-beta changes its conformation to reveal a
pseudo-2-fold symmetry on its surface structure so that it can
accommodate a symmetric dimer molecule.
EVOLUTION
Najafi-Shoushtari et al. (2010) identified the MIR33A gene within intron
16 of the SREBP2 gene. Brown et al. (2010) noted that the precursor for
mature miR33A is found within the same intron of SREBP2 from many animal
species, including large and small mammals, chickens, and frogs. There
is even a perfectly conserved mature form of miR33A in the single
SREBP-like gene of the fruit fly Drosophila melanogaster. The latter is
most remarkable because insects do not synthesize sterols; their single
SREBP gene controls fatty acid production. Moreover, the fruit fly
genome does not contain ABCA1. While miR33A exhibits uniform
conservation, miR33B (613486), present in intron 17 of the SREBP1 gene
(184756), is present only in large mammals.
MOLECULAR GENETICS
Yang et al. (1994) found a mutation in SREBF2 in a mutant CHO cell line
that is resistant to transcriptional repression by
25-hydroxycholesterol. The truncated gene product activates the LDL
receptor (606945) and HMG-CoA synthase (142940) genes independent of
sterols. The authors speculated that mutations or polymorphisms in
SREBF1 or SREBF2 could explain in part the wide variation in levels of
LDL-cholesterol seen in the general population.
Muller and Miserez (2002) presented evidence suggesting that mutations
in the SREBF2 gene are associated with hypercholesterolemia in man.
ANIMAL MODEL
In Abcg5 (605459)/Abcg8 (605460)-deficient mice, Yang et al. (2004)
demonstrated that accumulation of plant sterols perturbed cholesterol
homeostasis in the adrenal gland, with a 91% reduction in its
cholesterol content. Despite very low cholesterol levels, there was no
compensatory increase in cholesterol synthesis or in lipoprotein
receptor expression. Adrenal cholesterol levels returned to near-normal
levels in mice treated with ezetimibe, which blocks phytosterol
absorption. In cultured adrenal cells, stigmasterol but not sitosterol
inhibited SREBF2 processing and reduced cholesterol synthesis;
stigmasterol also activated the liver X receptor (see LXRA; 602423) in a
cell-based reporter assay. Yang et al. (2004) concluded that selected
dietary plant sterols disrupt cholesterol homeostasis by affecting 2
critical regulatory pathways of lipid metabolism.
Lens opacity-13 (lop13) is a spontaneous autosomal recessive mouse
mutant that exhibits nuclear cataracts. Merath et al. (2011) found that
mature cataracts developed in lop13 mice by 10 weeks of age and that
hypermature cataracts developed by 3 months of age. Histologic analysis
of lop13 eyes revealed swollen lens fiber cells and the presence of
bladder cells within the lens cortex, as well as morgagnian globules and
liquefied material at the lens posterior. Lens epithelial cells at the
anterior of the lens were normal. Lop13 mice also developed persistent
skin wounds at around 3 months of age, although lop13 skin was
indistinguishable from wildtype. Sequence analysis revealed a 3112C-T
mutation in exon 18 of the Srebf2 gene in lop13 mice, resulting in the
substitution of a highly conserved arginine within the Srebf2 regulatory
domain with cysteine (R1038C). Biochemical analysis revealed
significantly decreased cholesterol levels in lop13 brain and liver
compared with wildtype; however, serum cholesterol levels were normal.
Knockout of Srebf2 resulted in early embryonic lethality, but Srebf2 +/-
mice appeared normal. Since the adult ocular lens is nonvascularized,
Merath et al. (2011) hypothesized that SREBF2 and de novo cholesterol
synthesis are essential for normal lens function.
*FIELD* RF
1. Brown, M. S.; Ye, J.; Goldstein, J. L.: HDL miR-ed down by SREBP
introns. Science 328: 1495-1496, 2010.
2. DeBose-Boyd, R. A.; Brown, M. S.; Li, W.-P.; Nohturfft, A.; Goldstein,
J. L.; Espenshade, P. J.: Transport-dependent proteolysis of SREBP:
relocation of Site-1 protease from Golgi to ER obviates the need for
SREBP transport to Golgi. Cell 99: 703-712, 1999.
3. Hua, X.; Wu, J.; Goldstein, J. L.; Brown, M. S.; Hobbs, H. H.:
Structure of the human gene encoding sterol regulatory element binding
protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes
17p11.2 and 22q13. Genomics 25: 667-673, 1995.
4. Hua, X.; Yokoyama, C.; Wu, J.; Briggs, M. R.; Brown, M. S.; Goldstein,
J. L.; Wang, X.: SREBP-2, a second basic-helix-loop-helix-leucine
zipper protein that stimulates transcription by binding to a sterol
regulatory element. Proc. Nat. Acad. Sci. 90: 11603-11607, 1993.
5. Jeon, T.-I.; Zhu, B.; Larson, J. L.; Osborne, T. F.: SREBP-2 regulates
gut peptide secretion through intestinal bitter taste receptor signaling
in mice. J. Clin. Invest. 118: 3693-3700, 2008.
6. Lee, S. J.; Sekimoto, T.; Yamashita, E.; Nagoshi, E.; Nakagawa,
A.; Imamoto, N.; Yoshimura, M.; Sakai, H.; Chong, K. T.; Tsukihara,
T.; Yoneda, Y.: The structure of importin-beta bound to SREBP-2:
nuclear import of a transcription factor. Science 302: 1571-1575,
2003.
7. Merath, K. M.; Chang, B.; Dubielzig, R.; Jeannotte, R.; Sidjanin,
D. J.: A spontaneous mutation in Srebf2 leads to cataracts and persistent
skin wounds in the lens opacity 13 (lop13) mouse. Mammalian Genome 22:
661-673, 2011.
8. Miserez, A. R.; Cao, G.; Probst, L. C.; Hobbs, H. H.: Structure
of the human gene encoding sterol regulatory element binding protein
2 (SREBF2). Genomics 40: 31-40, 1997.
9. Muller, P. Y.; Miserez, A. R.: Identification of mutations in
the gene encoding sterol regulatory element binding protein (SREBP)-2
in hypercholesterolaemic subjects. J. Med. Genet. 39: 271-275, 2002.
10. Najafi-Shoushtari, S. H.; Kristo, F.; Li, Y.; Shioda, T.; Cohen,
D. E.; Gerszten, R. E.; Naar, A. M.: MicroRNA-33 and the SREBP host
genes cooperate to control cholesterol homeostasis. Science 328:
1566-1569, 2010.
11. Osborne, T. F.: CREating a SCAP-less liver keeps SREBPs pinned
in the ER membrane and prevents increased lipid synthesis in response
to low cholesterol and high insulin. Genes Dev. 15: 1873-1878, 2001.
12. Rayner, K. J.; Suarez, Y.; Davalos, A.; Parathath, S.; Fitzgerald,
M. L.; Tamehiro, N.; Fisher, E. A.; Moore, K. J.; Fernandez-Hernando,
C.: MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328:
1570-1573, 2010.
13. Shimano, H.; Shimomura, I.; Hammer, R. E.; Herz, J.; Goldstein,
J. L.; Brown, M. S.; Horton, J. D.: Elevated levels of SREBP-2 and
cholesterol synthesis in livers of mice homozygous for a targeted
disruption of the SREBP-1 gene. J. Clin. Invest. 100: 2115-2124,
1997.
14. Yang, C.; Yu, L.; Li, W.; Xu, F.; Cohen, J. C.; Hobbs, H. H.:
Disruption of cholesterol homeostasis by plant sterols. J. Clin.
Invest. 114: 813-822, 2004.
15. Yang, J.; Sato, R.; Goldstein, J. L.; Brown, M. S.: Sterol-resistant
transcription in CHO cells caused by gene rearrangement that truncates
SREBP-2. Genes Dev. 8: 1910-1919, 1994.
*FIELD* CN
Patricia A. Hartz - updated: 10/23/2012
Patricia A. Hartz - updated: 8/2/2010
Ada Hamosh - updated: 7/12/2010
Marla J. F. O'Neill - updated: 10/14/2004
Cassandra L. Kniffin - updated: 1/15/2004
Ada Hamosh - updated: 12/3/2003
Patricia A. Hartz - updated: 4/18/2002
Stylianos E. Antonarakis - updated: 1/19/2000
Rebekah S. Rasooly - updated: 3/5/1998
Victor A. McKusick - updated: 11/12/1997
*FIELD* CD
Victor A. McKusick: 4/5/1995
*FIELD* ED
mgross: 11/07/2012
mgross: 11/7/2012
terry: 10/23/2012
alopez: 3/8/2012
mgross: 8/10/2010
terry: 8/2/2010
alopez: 7/16/2010
terry: 7/12/2010
carol: 10/15/2004
terry: 10/14/2004
carol: 1/22/2004
ckniffin: 1/15/2004
alopez: 12/8/2003
terry: 12/3/2003
ckniffin: 6/5/2002
carol: 4/18/2002
mgross: 1/19/2000
alopez: 3/5/1998
mark: 11/13/1997
jenny: 11/12/1997
alopez: 7/10/1997
mark: 4/13/1995
mark: 4/12/1995
mark: 4/7/1995
mark: 4/5/1995
*RECORD*
*FIELD* NO
600481
*FIELD* TI
*600481 STEROL REGULATORY ELEMENT-BINDING TRANSCRIPTION FACTOR 2; SREBF2
;;STEROL REGULATORY ELEMENT-BINDING PROTEIN 2; SREBP2
read more*FIELD* TX
DESCRIPTION
The sterol regulatory element (SRE)-binding protein-2 (SREBP2) is
structurally related to SREBP1 (SREBF1; 184756), and both control
cholesterol homeostasis by stimulating transcription of sterol-regulated
genes (summary by Osborne, 2001).
CLONING
Hua et al. (1993) cloned SREBF2 from a HeLa cell cDNA library. The
deduced 1,141-amino acid protein has a calculated molecular mass of 124
kD. SREBF2 has an acidic N-terminal domain, a basic helix-loop-helix
leucine zipper (bHLH-ZIP) motif, and a long C terminus. It also has
histidine, glutamic acid, and arginine residues implicated in DNA
recognition by other bHLH-ZIP proteins. SREBF2 and SREBF1 share 47%
amino acid identity overall and 71% identity in the bHLH-ZIP region.
Northern blot analysis revealed a major SREBF2 transcript of 5.2 kb in
all tissues examined. A minor transcript of about 4.2 kb was also
observed.
Miserez et al. (1997) found that SREBP2 was expressed ubiquitously as 2
mRNAs (4.2 and 5.2 kb) that differ in their 3-prime untranslated regions
because of different polyadenylation signals.
GENE STRUCTURE
Miserez et al. (1997) found that the SREBF2 gene contains 19 exons and
spans 72 kb, with a sterol regulatory element in the promoter region.
MAPPING
Hua et al. (1995) isolated a genomic cosmid clone for SREBF2 and mapped
the gene to 22q13 by analysis of human/rodent somatic cell hybrids and
fluorescence in situ hybridization.
GENE FUNCTION
By transfection of human 293 cells, Hua et al. (1993) found that SREBF2,
like SREBF1, drove transcription from a reporter gene containing SRE1 in
both the presence or absence of sterols.
Cholesterol homeostasis in animal cells is achieved by regulated
cleavage of SREBPs, membrane-bound transcription factors. Proteolytic
release of the active domains of SREBPs from membranes requires a
sterol-sensing protein called SCAP (601510), which forms a complex with
SREBPs. In sterol-depleted cells, DeBose-Boyd et al. (1999) found that
SCAP escorts SREBPs from the endoplasmic reticulum (ER) to the Golgi,
where SREBPs are cleaved by site-1 protease (S1P; 603355). The authors
showed that sterols block this transport and abolish cleavage.
Relocating active S1P from Golgi to ER by treating cells with brefeldin
A or by fusing the ER retention signal KDEL to S1P obviated the SCAP
requirement and rendered cleavage insensitive to sterols. DeBose-Boyd et
al. (1999) concluded that transport-dependent proteolysis may be a
common mechanism to regulate the processing of membrane proteins.
Shimano et al. (1997) concluded that SREBP2 can replace SREBP1 in
regulating cholesterol synthesis in livers of mice and that the higher
potency of SREBP2 leads to excessive hepatic cholesterol synthesis in
these animals.
See review by Osborne (2001).
Najafi-Shoushtari et al. (2010) and Rayner et al. (2010) found that the
microRNA miR33 (612156) embedded within intron 16 of the SREBP2 gene
plays a role in control of cholesterol homeostasis through
posttranscriptional repression of the adenosine triphosphate-binding
cassette transporter A1 (ABCA1; 600046).
Jeon et al. (2008) found that the nuclear level of hepatic Srebp2 was
elevated in mice fed a diet supplemented with lovastatin and ezetimibe
(L/E) to limit dietary sterol absorption and reduce HMG-CoA reductase
(HMGCR; 142910) activity. Genomic promoter-wide ChIP-chip analysis
revealed that Srebp2 bound a number of promoters for genes encoding
bitter taste-responding type-2 taste receptors (T2Rs; see 604867), which
are expressed in gut enteroendocrine cells and in the tongue and oral
cavity. Sterol depletion in the mouse enteroendocrine cell line STC-1,
or expression of human SREBP2 in STC-1 cells, led to increased T2R
expression. T2R expression was also increased in the proximal small
intestine of L/E-treated mice. In contrast, T2R expression in the tongue
was not induced by L/E feeding. Jeon et al. (2008) proposed that a low
cholesterol diet may induce SREBP2-mediated activation of bitter
signaling in the gut to prevent absorption of potentially toxic bitter
substances in plant-derived foods, in addition to maximizing lipid
uptake.
BIOCHEMICAL FEATURES
- Crystal Structure
Lee et al. (2003) showed the crystal structure of importin-beta (see
602738) complexed with the active form of SREBP2. Importin-beta uses
characteristic long helices like a pair of chopsticks to interact with
an SREBP2 dimer. Importin-beta changes its conformation to reveal a
pseudo-2-fold symmetry on its surface structure so that it can
accommodate a symmetric dimer molecule.
EVOLUTION
Najafi-Shoushtari et al. (2010) identified the MIR33A gene within intron
16 of the SREBP2 gene. Brown et al. (2010) noted that the precursor for
mature miR33A is found within the same intron of SREBP2 from many animal
species, including large and small mammals, chickens, and frogs. There
is even a perfectly conserved mature form of miR33A in the single
SREBP-like gene of the fruit fly Drosophila melanogaster. The latter is
most remarkable because insects do not synthesize sterols; their single
SREBP gene controls fatty acid production. Moreover, the fruit fly
genome does not contain ABCA1. While miR33A exhibits uniform
conservation, miR33B (613486), present in intron 17 of the SREBP1 gene
(184756), is present only in large mammals.
MOLECULAR GENETICS
Yang et al. (1994) found a mutation in SREBF2 in a mutant CHO cell line
that is resistant to transcriptional repression by
25-hydroxycholesterol. The truncated gene product activates the LDL
receptor (606945) and HMG-CoA synthase (142940) genes independent of
sterols. The authors speculated that mutations or polymorphisms in
SREBF1 or SREBF2 could explain in part the wide variation in levels of
LDL-cholesterol seen in the general population.
Muller and Miserez (2002) presented evidence suggesting that mutations
in the SREBF2 gene are associated with hypercholesterolemia in man.
ANIMAL MODEL
In Abcg5 (605459)/Abcg8 (605460)-deficient mice, Yang et al. (2004)
demonstrated that accumulation of plant sterols perturbed cholesterol
homeostasis in the adrenal gland, with a 91% reduction in its
cholesterol content. Despite very low cholesterol levels, there was no
compensatory increase in cholesterol synthesis or in lipoprotein
receptor expression. Adrenal cholesterol levels returned to near-normal
levels in mice treated with ezetimibe, which blocks phytosterol
absorption. In cultured adrenal cells, stigmasterol but not sitosterol
inhibited SREBF2 processing and reduced cholesterol synthesis;
stigmasterol also activated the liver X receptor (see LXRA; 602423) in a
cell-based reporter assay. Yang et al. (2004) concluded that selected
dietary plant sterols disrupt cholesterol homeostasis by affecting 2
critical regulatory pathways of lipid metabolism.
Lens opacity-13 (lop13) is a spontaneous autosomal recessive mouse
mutant that exhibits nuclear cataracts. Merath et al. (2011) found that
mature cataracts developed in lop13 mice by 10 weeks of age and that
hypermature cataracts developed by 3 months of age. Histologic analysis
of lop13 eyes revealed swollen lens fiber cells and the presence of
bladder cells within the lens cortex, as well as morgagnian globules and
liquefied material at the lens posterior. Lens epithelial cells at the
anterior of the lens were normal. Lop13 mice also developed persistent
skin wounds at around 3 months of age, although lop13 skin was
indistinguishable from wildtype. Sequence analysis revealed a 3112C-T
mutation in exon 18 of the Srebf2 gene in lop13 mice, resulting in the
substitution of a highly conserved arginine within the Srebf2 regulatory
domain with cysteine (R1038C). Biochemical analysis revealed
significantly decreased cholesterol levels in lop13 brain and liver
compared with wildtype; however, serum cholesterol levels were normal.
Knockout of Srebf2 resulted in early embryonic lethality, but Srebf2 +/-
mice appeared normal. Since the adult ocular lens is nonvascularized,
Merath et al. (2011) hypothesized that SREBF2 and de novo cholesterol
synthesis are essential for normal lens function.
*FIELD* RF
1. Brown, M. S.; Ye, J.; Goldstein, J. L.: HDL miR-ed down by SREBP
introns. Science 328: 1495-1496, 2010.
2. DeBose-Boyd, R. A.; Brown, M. S.; Li, W.-P.; Nohturfft, A.; Goldstein,
J. L.; Espenshade, P. J.: Transport-dependent proteolysis of SREBP:
relocation of Site-1 protease from Golgi to ER obviates the need for
SREBP transport to Golgi. Cell 99: 703-712, 1999.
3. Hua, X.; Wu, J.; Goldstein, J. L.; Brown, M. S.; Hobbs, H. H.:
Structure of the human gene encoding sterol regulatory element binding
protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes
17p11.2 and 22q13. Genomics 25: 667-673, 1995.
4. Hua, X.; Yokoyama, C.; Wu, J.; Briggs, M. R.; Brown, M. S.; Goldstein,
J. L.; Wang, X.: SREBP-2, a second basic-helix-loop-helix-leucine
zipper protein that stimulates transcription by binding to a sterol
regulatory element. Proc. Nat. Acad. Sci. 90: 11603-11607, 1993.
5. Jeon, T.-I.; Zhu, B.; Larson, J. L.; Osborne, T. F.: SREBP-2 regulates
gut peptide secretion through intestinal bitter taste receptor signaling
in mice. J. Clin. Invest. 118: 3693-3700, 2008.
6. Lee, S. J.; Sekimoto, T.; Yamashita, E.; Nagoshi, E.; Nakagawa,
A.; Imamoto, N.; Yoshimura, M.; Sakai, H.; Chong, K. T.; Tsukihara,
T.; Yoneda, Y.: The structure of importin-beta bound to SREBP-2:
nuclear import of a transcription factor. Science 302: 1571-1575,
2003.
7. Merath, K. M.; Chang, B.; Dubielzig, R.; Jeannotte, R.; Sidjanin,
D. J.: A spontaneous mutation in Srebf2 leads to cataracts and persistent
skin wounds in the lens opacity 13 (lop13) mouse. Mammalian Genome 22:
661-673, 2011.
8. Miserez, A. R.; Cao, G.; Probst, L. C.; Hobbs, H. H.: Structure
of the human gene encoding sterol regulatory element binding protein
2 (SREBF2). Genomics 40: 31-40, 1997.
9. Muller, P. Y.; Miserez, A. R.: Identification of mutations in
the gene encoding sterol regulatory element binding protein (SREBP)-2
in hypercholesterolaemic subjects. J. Med. Genet. 39: 271-275, 2002.
10. Najafi-Shoushtari, S. H.; Kristo, F.; Li, Y.; Shioda, T.; Cohen,
D. E.; Gerszten, R. E.; Naar, A. M.: MicroRNA-33 and the SREBP host
genes cooperate to control cholesterol homeostasis. Science 328:
1566-1569, 2010.
11. Osborne, T. F.: CREating a SCAP-less liver keeps SREBPs pinned
in the ER membrane and prevents increased lipid synthesis in response
to low cholesterol and high insulin. Genes Dev. 15: 1873-1878, 2001.
12. Rayner, K. J.; Suarez, Y.; Davalos, A.; Parathath, S.; Fitzgerald,
M. L.; Tamehiro, N.; Fisher, E. A.; Moore, K. J.; Fernandez-Hernando,
C.: MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328:
1570-1573, 2010.
13. Shimano, H.; Shimomura, I.; Hammer, R. E.; Herz, J.; Goldstein,
J. L.; Brown, M. S.; Horton, J. D.: Elevated levels of SREBP-2 and
cholesterol synthesis in livers of mice homozygous for a targeted
disruption of the SREBP-1 gene. J. Clin. Invest. 100: 2115-2124,
1997.
14. Yang, C.; Yu, L.; Li, W.; Xu, F.; Cohen, J. C.; Hobbs, H. H.:
Disruption of cholesterol homeostasis by plant sterols. J. Clin.
Invest. 114: 813-822, 2004.
15. Yang, J.; Sato, R.; Goldstein, J. L.; Brown, M. S.: Sterol-resistant
transcription in CHO cells caused by gene rearrangement that truncates
SREBP-2. Genes Dev. 8: 1910-1919, 1994.
*FIELD* CN
Patricia A. Hartz - updated: 10/23/2012
Patricia A. Hartz - updated: 8/2/2010
Ada Hamosh - updated: 7/12/2010
Marla J. F. O'Neill - updated: 10/14/2004
Cassandra L. Kniffin - updated: 1/15/2004
Ada Hamosh - updated: 12/3/2003
Patricia A. Hartz - updated: 4/18/2002
Stylianos E. Antonarakis - updated: 1/19/2000
Rebekah S. Rasooly - updated: 3/5/1998
Victor A. McKusick - updated: 11/12/1997
*FIELD* CD
Victor A. McKusick: 4/5/1995
*FIELD* ED
mgross: 11/07/2012
mgross: 11/7/2012
terry: 10/23/2012
alopez: 3/8/2012
mgross: 8/10/2010
terry: 8/2/2010
alopez: 7/16/2010
terry: 7/12/2010
carol: 10/15/2004
terry: 10/14/2004
carol: 1/22/2004
ckniffin: 1/15/2004
alopez: 12/8/2003
terry: 12/3/2003
ckniffin: 6/5/2002
carol: 4/18/2002
mgross: 1/19/2000
alopez: 3/5/1998
mark: 11/13/1997
jenny: 11/12/1997
alopez: 7/10/1997
mark: 4/13/1995
mark: 4/12/1995
mark: 4/7/1995
mark: 4/5/1995