HMDH_HUMAN
ID HMDH_HUMAN Reviewed; 888 AA.
AC P04035; B7Z3Y9; Q8N190;
DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1986, sequence version 1.
DT 03-AUG-2022, entry version 238.
DE RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase;
DE Short=HMG-CoA reductase;
DE EC=1.1.1.34 {ECO:0000269|PubMed:21357570, ECO:0000269|PubMed:2991281, ECO:0000269|PubMed:6995544};
GN Name=HMGCR {ECO:0000312|HGNC:HGNC:5006};
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, AND CATALYTIC ACTIVITY.
RX PubMed=2991281; DOI=10.1016/s0021-9258(17)39242-6;
RA Luskey K.L., Stevens B.;
RT "Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains
RT responsible for catalytic activity and sterol-regulated degradation.";
RL J. Biol. Chem. 260:10271-10277(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Nakajima T., Iwaki K., Hamakubo T., Kodama T., Emi M.;
RT "Human HMG-CoA reductase gene.";
RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Rieder M.J., da Ponte S.H., Kuldanek S.A., Rajkumar N., Smith J.D.,
RA Toth E.J., Nickerson D.A.;
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Blood;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP ACTIVITY REGULATION, CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=6995544;
RA Brown M.S., Goldstein J.L.;
RT "Multivalent feedback regulation of HMG CoA reductase, a control mechanism
RT coordinating isoprenoid synthesis and cell growth.";
RL J. Lipid Res. 21:505-517(1980).
RN [8]
RP INTERACTION WITH INSIG1, AND UBIQUITINATION.
RX PubMed=12535518; DOI=10.1016/s1097-2765(02)00822-5;
RA Sever N., Yang T., Brown M.S., Goldstein J.L., DeBose-Boyd R.A.;
RT "Accelerated degradation of HMG CoA reductase mediated by binding of insig-
RT 1 to its sterol-sensing domain.";
RL Mol. Cell 11:25-33(2003).
RN [9]
RP SUBCELLULAR LOCATION.
RX PubMed=17180682; DOI=10.1007/s00418-006-0254-6;
RA Kovacs W.J., Tape K.N., Shackelford J.E., Duan X., Kasumov T.,
RA Kelleher J.K., Brunengraber H., Krisans S.K.;
RT "Localization of the pre-squalene segment of the isoprenoid biosynthetic
RT pathway in mammalian peroxisomes.";
RL Histochem. Cell Biol. 127:273-290(2007).
RN [10]
RP INTERACTION WITH INSIG1, UBIQUITINATION AT LYS-89 AND LYS-248,
RP GLYCOSYLATION, AND MUTAGENESIS OF 75-TYR--TYR-77; LYS-89 AND LYS-248.
RX PubMed=19458199; DOI=10.1091/mbc.e08-09-0953;
RA Leichner G.S., Avner R., Harats D., Roitelman J.;
RT "Dislocation of HMG-CoA reductase and Insig-1, two polytopic endoplasmic
RT reticulum proteins, en route to proteasomal degradation.";
RL Mol. Biol. Cell 20:3330-3341(2009).
RN [11]
RP UBIQUITINATION.
RX PubMed=21778231; DOI=10.1074/jbc.m111.278036;
RA Leichner G.S., Avner R., Harats D., Roitelman J.;
RT "Metabolically regulated endoplasmic reticulum-associated degradation of 3-
RT hydroxy-3-methylglutaryl-CoA reductase: evidence for requirement of a
RT geranylgeranylated protein.";
RL J. Biol. Chem. 286:32150-32161(2011).
RN [12]
RP CATALYTIC ACTIVITY, FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF
RP GLY-807.
RX PubMed=21357570; DOI=10.1194/jlr.m011817;
RA Cuccioloni M., Mozzicafreddo M., Spina M., Tran C.N., Falconi M.,
RA Eleuteri A.M., Angeletti M.;
RT "Epigallocatechin-3-gallate potently inhibits the in vitro activity of
RT hydroxy-3-methyl-glutaryl-CoA reductase.";
RL J. Lipid Res. 52:897-907(2011).
RN [13]
RP UBIQUITINATION.
RX PubMed=22143767; DOI=10.1073/pnas.1112831108;
RA Jo Y., Lee P.C., Sguigna P.V., DeBose-Boyd R.A.;
RT "Sterol-induced degradation of HMG CoA reductase depends on interplay of
RT two Insigs and two ubiquitin ligases, gp78 and Trc8.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:20503-20508(2011).
RN [14]
RP TISSUE SPECIFICITY (ISOFORMS 1; 2 AND 3), AND ALTERNATIVE SPLICING.
RX PubMed=22989091; DOI=10.1186/1471-2199-13-29;
RA Stormo C., Kringen M.K., Grimholt R.M., Berg J.P., Piehler A.P.;
RT "A novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) splice
RT variant with an alternative exon 1 potentially encoding an extended N-
RT terminus.";
RL BMC Mol. Biol. 13:29-29(2012).
RN [15]
RP INTERACTION WITH UBIAD1.
RX PubMed=23169578; DOI=10.1002/humu.22230;
RA Nickerson M.L., Bosley A.D., Weiss J.S., Kostiha B.N., Hirota Y.,
RA Brandt W., Esposito D., Kinoshita S., Wessjohann L., Morham S.G.,
RA Andresson T., Kruth H.S., Okano T., Dean M.;
RT "The UBIAD1 prenyltransferase links menaquione-4 synthesis to cholesterol
RT metabolic enzymes.";
RL Hum. Mutat. 34:317-329(2013).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-504, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-872, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 422-888, AND SUBUNIT.
RX PubMed=10698924; DOI=10.1093/emboj/19.5.819;
RA Istvan E.S., Palnitkar M., Buchanan S.K., Deisenhofer J.;
RT "Crystal structure of the catalytic portion of human HMG-CoA reductase:
RT insights into regulation of activity and catalysis.";
RL EMBO J. 19:819-830(2000).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 422-888 IN COMPLEX WITH COENZYME A
RP AND NADP.
RX PubMed=11349148; DOI=10.1126/science.1059344;
RA Istvan E.S., Deisenhofer J.;
RT "Structural mechanism for statin inhibition of HMG-CoA reductase.";
RL Science 292:1160-1164(2001).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.39 ANGSTROMS) OF 441-875 IN COMPLEX WITH
RP STATIN-BASED INHIBITORS.
RX PubMed=18540668; DOI=10.1021/jm7015057;
RA Sarver R.W., Bills E., Bolton G., Bratton L.D., Caspers N.L., Dunbar J.B.,
RA Harris M.S., Hutchings R.H., Kennedy R.M., Larsen S.D., Pavlovsky A.,
RA Pfefferkorn J.A., Bainbridge G.;
RT "Thermodynamic and structure guided design of statin based inhibitors of 3-
RT hydroxy-3-methylglutaryl coenzyme A reductase.";
RL J. Med. Chem. 51:3804-3813(2008).
RN [21]
RP VARIANT VAL-638.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions of
RT human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [22]
RP ERRATUM OF PUBMED:10391209.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
CC -!- FUNCTION: Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA
CC (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of
CC cholesterol and other isoprenoids, thus plays a critical role in
CC cellular cholesterol homeostasis (PubMed:2991281, PubMed:21357570,
CC PubMed:6995544). HMGCR is the main target of statins, a class of
CC cholesterol-lowering drugs (PubMed:11349148, PubMed:18540668).
CC {ECO:0000269|PubMed:11349148, ECO:0000269|PubMed:18540668,
CC ECO:0000269|PubMed:21357570, ECO:0000269|PubMed:2991281,
CC ECO:0000269|PubMed:6995544}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-mevalonate + CoA + 2 NADP(+) = (3S)-hydroxy-3-
CC methylglutaryl-CoA + 2 H(+) + 2 NADPH; Xref=Rhea:RHEA:15989,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:36464, ChEBI:CHEBI:43074,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.34;
CC Evidence={ECO:0000269|PubMed:21357570, ECO:0000269|PubMed:2991281,
CC ECO:0000269|PubMed:6995544};
CC -!- ACTIVITY REGULATION: Regulated by a negative feedback mechanism through
CC sterols and non-sterol metabolites derived from mevalonate
CC (PubMed:6995544). Phosphorylation at Ser-872 down-regulates the
CC catalytic activity (By similarity). Inhibited by statins, a class of
CC hypolipidemic agents used as pharmaceuticals to lower cholesterol
CC levels in individuals at risk from cardiovascular disease due to
CC hypercholesterolemia (PubMed:11349148, PubMed:18540668). Inhibition of
CC HMGCR in the liver stimulates the LDL-receptors, which results in an
CC increased clearance of LDL from the bloodstream and a decrease in blood
CC cholesterol levels (PubMed:11349148, PubMed:18540668). The first
CC results can be seen after one week of statin use and the effect is
CC maximal after four to six weeks (PubMed:11349148, PubMed:18540668).
CC {ECO:0000250|UniProtKB:P00347, ECO:0000269|PubMed:11349148,
CC ECO:0000269|PubMed:18540668, ECO:0000303|PubMed:6995544}.
CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
CC -!- SUBUNIT: Homotetramer (PubMed:10698924). Homodimer (PubMed:10698924).
CC Interacts (via its SSD) with INSIG1; the interaction, accelerated by
CC sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its
CC ubiquitination by the sterol-mediated ERAD pathway (PubMed:12535518,
CC PubMed:19458199). Interacts with UBIAD1 (PubMed:23169578).
CC {ECO:0000269|PubMed:10698924, ECO:0000269|PubMed:11349148,
CC ECO:0000269|PubMed:12535518, ECO:0000269|PubMed:19458199,
CC ECO:0000269|PubMed:23169578}.
CC -!- INTERACTION:
CC P04035; Q9Y5Z9: UBIAD1; NbExp=3; IntAct=EBI-465513, EBI-2819725;
CC P04035; Q9Y5Z9-1: UBIAD1; NbExp=5; IntAct=EBI-465513, EBI-6621921;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:17180682, ECO:0000305|PubMed:2991281}; Multi-pass
CC membrane protein {ECO:0000250|UniProtKB:P00347}. Peroxisome membrane
CC {ECO:0000269|PubMed:17180682}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P00347}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=HMGCR-1a {ECO:0000303|PubMed:22989091};
CC IsoId=P04035-1; Sequence=Displayed;
CC Name=2; Synonyms=HMGCR-1c {ECO:0000303|PubMed:22989091};
CC IsoId=P04035-2; Sequence=VSP_002207;
CC Name=3; Synonyms=HMGCR-1b {ECO:0000303|PubMed:22989091};
CC IsoId=P04035-3; Sequence=VSP_046492;
CC -!- TISSUE SPECIFICITY: [Isoform 1]: Ubiquitously expressed with the
CC highest levels in the cerebellum, fetal brain, testis, skin and adrenal
CC gland. {ECO:0000269|PubMed:22989091}.
CC -!- TISSUE SPECIFICITY: [Isoform 2]: Detected in the cerebellum, fetal
CC brain, testis and adrenal gland. {ECO:0000269|PubMed:22989091}.
CC -!- TISSUE SPECIFICITY: [Isoform 3]: Low abundance except in skin,
CC esophagus, and uterine cervix. {ECO:0000269|PubMed:22989091}.
CC -!- PTM: N-glycosylated. Deglycosylated by NGLY1 on release from the
CC endoplasmic reticulum (ER) in a sterol-mediated manner.
CC {ECO:0000269|PubMed:19458199}.
CC -!- PTM: Undergoes sterol-mediated ubiquitination and ER-associated
CC degradation (ERAD) (PubMed:12535518, PubMed:19458199, PubMed:21778231).
CC Accumulation of sterols in the endoplasmic reticulum (ER) membrane,
CC triggers binding of the reductase to the ER membrane protein INSIG1 or
CC INSIG2 (PubMed:12535518, PubMed:19458199, PubMed:21778231,
CC PubMed:22143767). The INSIG1 binding leads to the recruitment of the
CC ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating
CC ubiquitination of the reductase (PubMed:12535518, PubMed:19458199,
CC PubMed:21778231). The ubiquitinated reductase is then extracted from
CC the ER membrane and delivered to cytosolic 26S proteosomes by a
CC mechanism probably mediated by the ATPase Valosin-containing protein
CC VCP/p97 (PubMed:12535518, PubMed:19458199, PubMed:21778231). The
CC INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139,
CC initiating ubiquitination of the reductase (PubMed:22143767). Lys-248
CC is the main site of ubiquitination (PubMed:19458199). Ubiquitination is
CC enhanced by the presence of a geranylgeranylated protein
CC (PubMed:21778231). {ECO:0000269|PubMed:12535518,
CC ECO:0000269|PubMed:19458199, ECO:0000269|PubMed:21778231,
CC ECO:0000269|PubMed:22143767}.
CC -!- PTM: Phosphorylated. Phosphorylation at Ser-872 reduces the catalytic
CC activity. {ECO:0000250|UniProtKB:P00347}.
CC -!- SIMILARITY: Belongs to the HMG-CoA reductase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAH12375.1; Type=Frameshift; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; M11058; AAA52679.1; -; mRNA.
DR EMBL; AF273765; AAG21343.1; -; Genomic_DNA.
DR EMBL; AF273754; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AF273755; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AF273756; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AF273757; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AF273758; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AF273759; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AF273760; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AF273761; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AF273762; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AF273763; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AF273764; AAG21343.1; JOINED; Genomic_DNA.
DR EMBL; AY321356; AAP72015.1; -; Genomic_DNA.
DR EMBL; AK296499; BAH12375.1; ALT_FRAME; mRNA.
DR EMBL; AC008897; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC033692; AAH33692.1; -; mRNA.
DR CCDS; CCDS4027.1; -. [P04035-1]
DR CCDS; CCDS47234.1; -. [P04035-2]
DR PIR; A00356; RDHUE.
DR RefSeq; NP_000850.1; NM_000859.2. [P04035-1]
DR RefSeq; NP_001124468.1; NM_001130996.1. [P04035-2]
DR RefSeq; XP_011541659.1; XM_011543357.1. [P04035-3]
DR RefSeq; XP_011541660.1; XM_011543358.1. [P04035-1]
DR PDB; 1DQ8; X-ray; 2.10 A; A/B/C/D=426-888.
DR PDB; 1DQ9; X-ray; 2.80 A; A/B/C/D=426-888.
DR PDB; 1DQA; X-ray; 2.00 A; A/B/C/D=426-888.
DR PDB; 1HW8; X-ray; 2.10 A; A/B/C/D=426-888.
DR PDB; 1HW9; X-ray; 2.33 A; A/B/C/D=426-888.
DR PDB; 1HWI; X-ray; 2.30 A; A/B/C/D=426-888.
DR PDB; 1HWJ; X-ray; 2.26 A; A/B/C/D=426-888.
DR PDB; 1HWK; X-ray; 2.22 A; A/B/C/D=426-888.
DR PDB; 1HWL; X-ray; 2.10 A; A/B/C/D=426-888.
DR PDB; 2Q1L; X-ray; 2.05 A; A/B/C/D=441-875.
DR PDB; 2Q6B; X-ray; 2.00 A; A/B/C/D=441-875.
DR PDB; 2Q6C; X-ray; 2.00 A; A/B/C/D=441-875.
DR PDB; 2R4F; X-ray; 1.70 A; A/B/C/D=441-875.
DR PDB; 3BGL; X-ray; 2.23 A; A/B/C/D=441-875.
DR PDB; 3CCT; X-ray; 2.12 A; A/B/C/D=441-875.
DR PDB; 3CCW; X-ray; 2.10 A; A/B/C/D=441-875.
DR PDB; 3CCZ; X-ray; 1.70 A; A/B/C/D=441-875.
DR PDB; 3CD0; X-ray; 2.40 A; A/B/C/D=441-875.
DR PDB; 3CD5; X-ray; 2.39 A; A/B/C/D=441-875.
DR PDB; 3CD7; X-ray; 2.05 A; A/B/C/D=441-875.
DR PDB; 3CDA; X-ray; 2.07 A; A/B/C/D=441-875.
DR PDB; 3CDB; X-ray; 2.30 A; A/B/C/D=441-875.
DR PDBsum; 1DQ8; -.
DR PDBsum; 1DQ9; -.
DR PDBsum; 1DQA; -.
DR PDBsum; 1HW8; -.
DR PDBsum; 1HW9; -.
DR PDBsum; 1HWI; -.
DR PDBsum; 1HWJ; -.
DR PDBsum; 1HWK; -.
DR PDBsum; 1HWL; -.
DR PDBsum; 2Q1L; -.
DR PDBsum; 2Q6B; -.
DR PDBsum; 2Q6C; -.
DR PDBsum; 2R4F; -.
DR PDBsum; 3BGL; -.
DR PDBsum; 3CCT; -.
DR PDBsum; 3CCW; -.
DR PDBsum; 3CCZ; -.
DR PDBsum; 3CD0; -.
DR PDBsum; 3CD5; -.
DR PDBsum; 3CD7; -.
DR PDBsum; 3CDA; -.
DR PDBsum; 3CDB; -.
DR AlphaFoldDB; P04035; -.
DR SMR; P04035; -.
DR BioGRID; 109399; 138.
DR ELM; P04035; -.
DR IntAct; P04035; 18.
DR STRING; 9606.ENSP00000287936; -.
DR BindingDB; P04035; -.
DR ChEMBL; CHEMBL402; -.
DR DrugBank; DB03169; (S)-Hmg-Coa.
DR DrugBank; DB04447; 1,4-Dithiothreitol.
DR DrugBank; DB01076; Atorvastatin.
DR DrugBank; DB09061; Cannabidiol.
DR DrugBank; DB00439; Cerivastatin.
DR DrugBank; DB01992; Coenzyme A.
DR DrugBank; DB01095; Fluvastatin.
DR DrugBank; DB00227; Lovastatin.
DR DrugBank; DB14009; Medical Cannabis.
DR DrugBank; DB04377; Meglutol.
DR DrugBank; DB06693; Mevastatin.
DR DrugBank; DB14011; Nabiximols.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB03461; Nicotinamide adenine dinucleotide phosphate.
DR DrugBank; DB08860; Pitavastatin.
DR DrugBank; DB00175; Pravastatin.
DR DrugBank; DB01098; Rosuvastatin.
DR DrugBank; DB00641; Simvastatin.
DR DrugBank; DB05317; TAK-475.
DR DrugBank; DB09270; Ubidecarenone.
DR DrugCentral; P04035; -.
DR GuidetoPHARMACOLOGY; 639; -.
DR SwissLipids; SLP:000001246; -.
DR TCDB; 2.A.6.6.5; the resistance-nodulation-cell division (rnd) superfamily.
DR GlyConnect; 983; 3 N-Linked glycans (1 site).
DR GlyGen; P04035; 2 sites, 3 N-linked glycans (1 site).
DR iPTMnet; P04035; -.
DR MetOSite; P04035; -.
DR PhosphoSitePlus; P04035; -.
DR SwissPalm; P04035; -.
DR BioMuta; HMGCR; -.
DR DMDM; 123343; -.
DR EPD; P04035; -.
DR jPOST; P04035; -.
DR MassIVE; P04035; -.
DR MaxQB; P04035; -.
DR PaxDb; P04035; -.
DR PeptideAtlas; P04035; -.
DR PRIDE; P04035; -.
DR ProteomicsDB; 51634; -. [P04035-1]
DR ProteomicsDB; 51635; -. [P04035-2]
DR Antibodypedia; 24380; 358 antibodies from 35 providers.
DR DNASU; 3156; -.
DR Ensembl; ENST00000287936.9; ENSP00000287936.4; ENSG00000113161.17. [P04035-1]
DR Ensembl; ENST00000343975.9; ENSP00000340816.5; ENSG00000113161.17. [P04035-2]
DR Ensembl; ENST00000511206.5; ENSP00000426745.1; ENSG00000113161.17. [P04035-1]
DR Ensembl; ENST00000680940.1; ENSP00000505561.1; ENSG00000113161.17. [P04035-1]
DR Ensembl; ENST00000681271.1; ENSP00000505805.1; ENSG00000113161.17. [P04035-1]
DR Ensembl; ENST00000681410.1; ENSP00000506232.1; ENSG00000113161.17. [P04035-1]
DR GeneID; 3156; -.
DR KEGG; hsa:3156; -.
DR MANE-Select; ENST00000287936.9; ENSP00000287936.4; NM_000859.3; NP_000850.1.
DR UCSC; uc003kdp.4; human. [P04035-1]
DR CTD; 3156; -.
DR DisGeNET; 3156; -.
DR GeneCards; HMGCR; -.
DR HGNC; HGNC:5006; HMGCR.
DR HPA; ENSG00000113161; Tissue enhanced (liver).
DR MIM; 142910; gene+phenotype.
DR neXtProt; NX_P04035; -.
DR OpenTargets; ENSG00000113161; -.
DR PharmGKB; PA189; -.
DR VEuPathDB; HostDB:ENSG00000113161; -.
DR eggNOG; KOG2480; Eukaryota.
DR GeneTree; ENSGT00940000155305; -.
DR HOGENOM; CLU_001734_0_1_1; -.
DR InParanoid; P04035; -.
DR OMA; CHGWSQS; -.
DR OrthoDB; 907394at2759; -.
DR PhylomeDB; P04035; -.
DR TreeFam; TF105362; -.
DR BioCyc; MetaCyc:HS03652-MON; -.
DR BRENDA; 1.1.1.34; 2681.
DR PathwayCommons; P04035; -.
DR Reactome; R-HSA-191273; Cholesterol biosynthesis.
DR Reactome; R-HSA-1989781; PPARA activates gene expression. [P04035-1]
DR Reactome; R-HSA-2426168; Activation of gene expression by SREBF (SREBP). [P04035-1]
DR Reactome; R-HSA-9619665; EGR2 and SOX10-mediated initiation of Schwann cell myelination.
DR SABIO-RK; P04035; -.
DR SignaLink; P04035; -.
DR SIGNOR; P04035; -.
DR UniPathway; UPA00058; UER00103.
DR BioGRID-ORCS; 3156; 632 hits in 1083 CRISPR screens.
DR ChiTaRS; HMGCR; human.
DR EvolutionaryTrace; P04035; -.
DR GeneWiki; HMG-CoA_reductase; -.
DR GenomeRNAi; 3156; -.
DR Pharos; P04035; Tclin.
DR PRO; PR:P04035; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; P04035; protein.
DR Bgee; ENSG00000113161; Expressed in adrenal tissue and 198 other tissues.
DR ExpressionAtlas; P04035; baseline and differential.
DR Genevisible; P04035; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005778; C:peroxisomal membrane; IDA:UniProtKB.
DR GO; GO:0120225; F:coenzyme A binding; IDA:UniProtKB.
DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IDA:UniProtKB.
DR GO; GO:0070402; F:NADPH binding; IDA:UniProtKB.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IDA:CACAO.
DR GO; GO:0015936; P:coenzyme A metabolic process; IEA:InterPro.
DR GO; GO:0008299; P:isoprenoid biosynthetic process; IBA:GO_Central.
DR GO; GO:1900222; P:negative regulation of amyloid-beta clearance; ISS:ARUK-UCL.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; ISS:ARUK-UCL.
DR GO; GO:0050709; P:negative regulation of protein secretion; ISS:ARUK-UCL.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR GO; GO:0008542; P:visual learning; IEA:Ensembl.
DR CDD; cd00643; HMG-CoA_reductase_classI; 1.
DR DisProt; DP02709; -.
DR Gene3D; 1.10.3270.10; -; 1.
DR Gene3D; 3.30.70.420; -; 1.
DR Gene3D; 3.90.770.10; -; 1.
DR InterPro; IPR002202; HMG_CoA_Rdtase.
DR InterPro; IPR023074; HMG_CoA_Rdtase_cat_sf.
DR InterPro; IPR023076; HMG_CoA_Rdtase_CS.
DR InterPro; IPR004554; HMG_CoA_Rdtase_eu_arc.
DR InterPro; IPR004816; HMG_CoA_Rdtase_metazoan.
DR InterPro; IPR023282; HMG_CoA_Rdtase_N.
DR InterPro; IPR009023; HMG_CoA_Rdtase_NAD(P)-bd_sf.
DR InterPro; IPR009029; HMG_CoA_Rdtase_sub-bd_dom_sf.
DR InterPro; IPR000731; SSD.
DR PANTHER; PTHR10572; PTHR10572; 1.
DR Pfam; PF00368; HMG-CoA_red; 1.
DR Pfam; PF12349; Sterol-sensing; 1.
DR PRINTS; PR00071; HMGCOARDTASE.
DR SUPFAM; SSF55035; SSF55035; 1.
DR SUPFAM; SSF56542; SSF56542; 1.
DR TIGRFAMs; TIGR00920; 2A060605; 1.
DR TIGRFAMs; TIGR00533; HMG_CoA_R_NADP; 1.
DR PROSITE; PS00066; HMG_COA_REDUCTASE_1; 1.
DR PROSITE; PS00318; HMG_COA_REDUCTASE_2; 1.
DR PROSITE; PS01192; HMG_COA_REDUCTASE_3; 1.
DR PROSITE; PS50065; HMG_COA_REDUCTASE_4; 1.
DR PROSITE; PS50156; SSD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cholesterol biosynthesis;
KW Cholesterol metabolism; Endoplasmic reticulum; Glycoprotein;
KW Isopeptide bond; Lipid biosynthesis; Lipid metabolism; Membrane; NADP;
KW Oxidoreductase; Peroxisome; Phosphoprotein; Reference proteome;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..888
FT /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase"
FT /id="PRO_0000114419"
FT TOPO_DOM 1..9
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TRANSMEM 10..39
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TOPO_DOM 40..56
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TRANSMEM 57..78
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TOPO_DOM 79..89
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TRANSMEM 90..114
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TOPO_DOM 115..123
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TRANSMEM 124..149
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TOPO_DOM 150..159
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TRANSMEM 160..187
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TOPO_DOM 188..191
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TRANSMEM 192..220
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TOPO_DOM 221..248
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TRANSMEM 249..275
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TOPO_DOM 276..314
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TRANSMEM 315..339
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT TOPO_DOM 340..888
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT DOMAIN 61..218
FT /note="SSD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00199"
FT MOTIF 75..78
FT /note="INSIG-binding motif"
FT /evidence="ECO:0000269|PubMed:19458199"
FT ACT_SITE 559
FT /note="Charge relay system"
FT /evidence="ECO:0000303|PubMed:10698924,
FT ECO:0000303|PubMed:11349148"
FT ACT_SITE 691
FT /note="Charge relay system"
FT /evidence="ECO:0000303|PubMed:10698924,
FT ECO:0000303|PubMed:11349148"
FT ACT_SITE 767
FT /note="Charge relay system"
FT /evidence="ECO:0000303|PubMed:10698924,
FT ECO:0000303|PubMed:11349148"
FT ACT_SITE 866
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10003"
FT BINDING 565..571
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:11349148,
FT ECO:0007744|PDB:1DQA"
FT BINDING 626..628
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:11349148,
FT ECO:0007744|PDB:1DQA"
FT BINDING 653..661
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:11349148,
FT ECO:0007744|PDB:1DQA"
FT BINDING 720..722
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:11349148,
FT ECO:0007744|PDB:1DQA"
FT BINDING 865..866
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000269|PubMed:11349148,
FT ECO:0007744|PDB:1DQA"
FT BINDING 870..871
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:11349148,
FT ECO:0007744|PDB:1DQA"
FT MOD_RES 504
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 872
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P00347,
FT ECO:0007744|PubMed:24275569"
FT CARBOHYD 281
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 296
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CROSSLNK 89
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:19458199"
FT CROSSLNK 248
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:19458199"
FT VAR_SEQ 1
FT /note="M -> MQWMSHTRERDAGSKDSVATM (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046492"
FT VAR_SEQ 522..574
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_002207"
FT VARIANT 638
FT /note="I -> V (in dbSNP:rs5908)"
FT /evidence="ECO:0000269|PubMed:10391209"
FT /id="VAR_011954"
FT MUTAGEN 75..77
FT /note="YIY->AIA: Reduced sterol-mediated release from the
FT ER. Not deglycosylated in response to sterols."
FT /evidence="ECO:0000269|PubMed:19458199"
FT MUTAGEN 89
FT /note="K->R: Abolishes sterol-mediated ubiquitination and
FT degradation; when associated with R-248."
FT /evidence="ECO:0000269|PubMed:19458199"
FT MUTAGEN 248
FT /note="K->R: Abolishes sterol-mediated ubiquitination and
FT degradation; when associated with R-89."
FT /evidence="ECO:0000269|PubMed:19458199"
FT MUTAGEN 807
FT /note="G->D: Does not affect hydroxymethylglutaryl-CoA
FT reductase activity."
FT /evidence="ECO:0000269|PubMed:21357570"
FT HELIX 445..453
FT /evidence="ECO:0007829|PDB:2R4F"
FT TURN 455..457
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 458..460
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 464..472
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 474..476
FT /evidence="ECO:0007829|PDB:3CDA"
FT HELIX 478..480
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 481..484
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 485..487
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 488..502
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 503..505
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 508..511
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 515..517
FT /evidence="ECO:0007829|PDB:1DQ9"
FT HELIX 519..521
FT /evidence="ECO:0007829|PDB:2R4F"
FT TURN 522..525
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 528..546
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 549..556
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 562..575
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 579..590
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 593..595
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 599..610
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 612..623
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 635..639
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 642..650
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 657..674
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 679..683
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 686..688
FT /evidence="ECO:0007829|PDB:1DQA"
FT HELIX 695..700
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 703..712
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 714..719
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 721..723
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 725..736
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 738..742
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 746..752
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 753..763
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 768..770
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 771..774
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 777..785
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 790..800
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 804..806
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 807..810
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 812..820
FT /evidence="ECO:0007829|PDB:2R4F"
FT STRAND 828..830
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 833..859
FT /evidence="ECO:0007829|PDB:2R4F"
FT HELIX 862..869
FT /evidence="ECO:0007829|PDB:1DQA"
SQ SEQUENCE 888 AA; 97476 MW; 49B610DCCCFA26B6 CRC64;
MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC PKFEEDVLSS
DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI FSSFVFSTVV IHFLDKELTG
LNEALPFFLL LIDLSRASTL AKFALSSNSQ DEVRENIARG MAILGPTFTL DALVECLVIG
VGTMSGVRQL EIMCCFGCMS VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR
VLEEEENKPN PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTADTSKVS LGLDENVSKR
IEPSVSLWQF YLSKMISMDI EQVITLSLAL LLAVKYIFFE QTETESTLSL KNPITSPVVT
QKKVPDNCCR REPMLVRNNQ KCDSVEEETG INRERKVEVI KPLVAETDTP NRATFVVGNS
SLLDTSSVLV TQEPEIELPR EPRPNEECLQ ILGNAEKGAK FLSDAEIIQL VNAKHIPAYK
LETLMETHER GVSIRRQLLS KKLSEPSSLQ YLPYRDYNYS LVMGACCENV IGYMPIPVGV
AGPLCLDEKE FQVPMATTEG CLVASTNRGC RAIGLGGGAS SRVLADGMTR GPVVRLPRAC
DSAEVKAWLE TSEGFAVIKE AFDSTSRFAR LQKLHTSIAG RNLYIRFQSR SGDAMGMNMI
SKGTEKALSK LHEYFPEMQI LAVSGNYCTD KKPAAINWIE GRGKSVVCEA VIPAKVVREV
LKTTTEAMIE VNINKNLVGS AMAGSIGGYN AHAANIVTAI YIACGQDAAQ NVGSSNCITL
MEASGPTNED LYISCTMPSI EIGTVGGGTN LLPQQACLQM LGVQGACKDN PGENARQLAR
IVCGTVMAGE LSLMAALAAG HLVKSHMIHN RSKINLQDLQ GACTKKTA
