HMDH_CRIGR
ID HMDH_CRIGR Reviewed; 887 AA.
AC P00347;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 25-MAY-2022, entry version 160.
DE RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase;
DE Short=HMG-CoA reductase;
DE EC=1.1.1.34 {ECO:0000250|UniProtKB:P04035};
GN Name=HMGCR;
OS Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Cricetulus.
OX NCBI_TaxID=10029;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND SUBCELLULAR LOCATION.
RX PubMed=6546784; DOI=10.1038/308613a0;
RA Chin D.J., Gil G., Russell D.W., Liscum L., Luskey K.L., Basu S.K.,
RA Okayama H., Berg P., Goldstein J.L., Brown M.S.;
RT "Nucleotide sequence of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, a
RT glycoprotein of endoplasmic reticulum.";
RL Nature 308:613-617(1984).
RN [2]
RP GLYCOSYLATION, AND STRUCTURE OF CARBOHYDRATES.
RX PubMed=6580634; DOI=10.1073/pnas.80.23.7165;
RA Liscum L., Cummings R.D., Anderson R.G., DeMartino G.N., Goldstein J.L.,
RA Brown M.S.;
RT "3-Hydroxy-3-methylglutaryl-CoA reductase: a transmembrane glycoprotein of
RT the endoplasmic reticulum with N-linked 'high-mannose' oligosaccharides.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:7165-7169(1983).
RN [3]
RP GENE STRUCTURE.
RX PubMed=6088070; DOI=10.1016/0092-8674(84)90549-x;
RA Reynolds G.A., Basu S.K., Osborne T.F., Chin D.J., Gil G., Brown M.S.,
RA Goldstein J.L., Luskey K.L.;
RT "HMG CoA reductase: a negatively regulated gene with unusual promoter and
RT 5' untranslated regions.";
RL Cell 38:275-285(1984).
RN [4]
RP DOMAINS.
RX PubMed=3965461; DOI=10.1016/s0021-9258(18)89764-2;
RA Liscum L., Finer-Moore J., Stroud R.M., Luskey K.L., Brown M.S.,
RA Goldstein J.L.;
RT "Domain structure of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a
RT glycoprotein of the endoplasmic reticulum.";
RL J. Biol. Chem. 260:522-530(1985).
RN [5]
RP TOPOLOGY.
RX PubMed=1374417; DOI=10.1083/jcb.117.5.959;
RA Roitelman J., Olender E.H., Bar-Nun S., Dunn W.A. Jr., Simoni R.D.;
RT "Immunological evidence for eight spans in the membrane domain of 3-
RT hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme
RT degradation in the endoplasmic reticulum.";
RL J. Cell Biol. 117:959-973(1992).
RN [6]
RP PHOSPHORYLATION AT SER-871, MUTAGENESIS OF SER-871, ACTIVITY REGULATION,
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=8415689; DOI=10.1073/pnas.90.20.9261;
RA Sato R., Goldstein J.L., Brown M.S.;
RT "Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-CoA
RT reductase prevents phosphorylation by AMP-activated kinase and blocks
RT inhibition of sterol synthesis induced by ATP depletion.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:9261-9265(1993).
RN [7]
RP UBIQUITINATION AT LYS-89 AND LYS-248, AND MUTAGENESIS OF TYR-75; ILE-76;
RP TYR-77; PHE-78; LYS-89 AND LYS-248.
RX PubMed=14563840; DOI=10.1074/jbc.m310053200;
RA Sever N., Song B.L., Yabe D., Goldstein J.L., Brown M.S., DeBose-Boyd R.A.;
RT "Insig-dependent ubiquitination and degradation of mammalian 3-hydroxy-3-
RT methylglutaryl-CoA reductase stimulated by sterols and geranylgeraniol.";
RL J. Biol. Chem. 278:52479-52490(2003).
RN [8]
RP UBIQUITINATION AT LYS-89 AND LYS-248.
RX PubMed=15247208; DOI=10.1074/jbc.m405935200;
RA Doolman R., Leichner G.S., Avner R., Roitelman J.;
RT "Ubiquitin is conjugated by membrane ubiquitin ligase to three sites,
RT including the N terminus, in transmembrane region of mammalian 3-hydroxy-3-
RT methylglutaryl coenzyme A reductase: implications for sterol-regulated
RT enzyme degradation.";
RL J. Biol. Chem. 279:38184-38193(2004).
RN [9]
RP UBIQUITINATION, INTERACTION WITH INSIG1, AND MUTAGENESIS OF SER-60; GLY-87
RP AND ALA-333.
RX PubMed=17090658; DOI=10.1194/jlr.m600476-jlr200;
RA Lee P.C., Nguyen A.D., Debose-Boyd R.A.;
RT "Mutations within the membrane domain of HMG-CoA reductase confer
RT resistance to sterol-accelerated degradation.";
RL J. Lipid Res. 48:318-327(2007).
RN [10]
RP UBIQUITINATION.
RX PubMed=29374057; DOI=10.1074/jbc.ra117.001260;
RA Jiang L.Y., Jiang W., Tian N., Xiong Y.N., Liu J., Wei J., Wu K.Y., Luo J.,
RA Shi X.J., Song B.L.;
RT "Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced
RT degradation of HMG-CoA reductase.";
RL J. Biol. Chem. 293:4047-4055(2018).
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. {ECO:0000250|UniProtKB:P04035}.
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:0000250|UniProtKB:P04035};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15991;
CC Evidence={ECO:0000250|UniProtKB:P04035};
CC -!- ACTIVITY REGULATION: Regulated by a negative feedback mechanism through
CC sterols and non-sterol metabolites derived from mevalonate (By
CC similarity). Phosphorylation at Ser-871 down-regulates the catalytic
CC activity (PubMed:8415689). {ECO:0000250|UniProtKB:P04035,
CC ECO:0000269|PubMed:8415689}.
CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
CC -!- SUBUNIT: Homotetramer. Homodimer. Interacts (via its SSD) with INSIG1;
CC the interaction, accelerated by sterols, leads to the recruitment of
CC HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD
CC pathway (PubMed:17090658). Interacts with UBIAD1 (By similarity).
CC {ECO:0000250|UniProtKB:P04035, ECO:0000269|PubMed:17090658}.
CC -!- INTERACTION:
CC P00347; O94905: ERLIN2; Xeno; NbExp=2; IntAct=EBI-11426687, EBI-4400770;
CC P00347; O15503: INSIG1; Xeno; NbExp=2; IntAct=EBI-11426687, EBI-6252425;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:6546784}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:1374417}. Peroxisome membrane
CC {ECO:0000250|UniProtKB:P04035}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:1374417}.
CC -!- PTM: N-glycosylated. Glycosylated with high mannose chains including
CC Man(6)(GlcNAc)(2), Man(7)(GlcNAc)(2) and Man(8)(GlcNAc)(2)
CC (PubMed:6580634). Deglycosylated by NGLY1 on release from the
CC endoplasmic reticulum (ER) in a sterol-mediated manner (By similarity).
CC {ECO:0000250|UniProtKB:P04035, ECO:0000269|PubMed:6580634}.
CC -!- PTM: Undergoes sterol-mediated ubiquitination and ER-associated
CC degradation (ERAD) (PubMed:14563840, PubMed:15247208, PubMed:17090658,
CC PubMed:29374057). Accumulation of sterols in the endoplasmic reticulum
CC (ER) membrane, triggers binding of the reductase to the ER membrane
CC protein INSIG1 or INSIG2 (PubMed:14563840, PubMed:17090658). The INSIG1
CC binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78,
CC RNF139 or RNF145, initiating ubiquitination of the reductase
CC (PubMed:14563840, PubMed:29374057). The ubiquitinated reductase is then
CC extracted from the ER membrane and delivered to cytosolic 26S
CC proteosomes by a mechanism probably mediated by the ATPase Valosin-
CC containing protein VCP/p97 (PubMed:14563840). The INSIG2-binding leads
CC to the recruitment of the ubiquitin ligase RNF139, initiating
CC ubiquitination of the reductase (By similarity). Lys-248 is the main
CC site of ubiquitination (PubMed:14563840, PubMed:15247208).
CC Ubiquitination is enhanced by the presence of a geranylgeranylated
CC protein (By similarity). {ECO:0000250|UniProtKB:P04035,
CC ECO:0000269|PubMed:14563840, ECO:0000269|PubMed:15247208,
CC ECO:0000269|PubMed:17090658, ECO:0000269|PubMed:29374057}.
CC -!- PTM: Phosphorylated. Phosphorylation at Ser-871 reduces the catalytic
CC activity. {ECO:0000269|PubMed:8415689}.
CC -!- SIMILARITY: Belongs to the HMG-CoA reductase family. {ECO:0000305}.
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DR EMBL; L00183; AAA36989.1; -; Genomic_DNA.
DR EMBL; L00166; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00169; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00170; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00171; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00173; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00176; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00177; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00178; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00179; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00180; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00181; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; L00182; AAA36989.1; JOINED; Genomic_DNA.
DR EMBL; X00494; CAA25189.1; -; Genomic_DNA.
DR PIR; A93328; RDHYE.
DR RefSeq; XP_003508040.1; XM_003507992.3.
DR RefSeq; XP_007634389.1; XM_007636199.2.
DR RefSeq; XP_007646809.1; XM_007648619.2.
DR AlphaFoldDB; P00347; -.
DR SMR; P00347; -.
DR IntAct; P00347; 4.
DR STRING; 10029.XP_007634387.1; -.
DR iPTMnet; P00347; -.
DR Ensembl; ENSCGRT00001020833; ENSCGRP00001016589; ENSCGRG00001016870.
DR GeneID; 100756363; -.
DR KEGG; cge:100756363; -.
DR CTD; 3156; -.
DR eggNOG; KOG2480; Eukaryota.
DR GeneTree; ENSGT00940000155305; -.
DR OMA; CHGWSQS; -.
DR OrthoDB; 907394at2759; -.
DR BRENDA; 1.1.1.34; 1309.
DR UniPathway; UPA00058; UER00103.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005778; C:peroxisomal membrane; ISS:UniProtKB.
DR GO; GO:0120225; F:coenzyme A binding; IEA:Ensembl.
DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IDA:UniProtKB.
DR GO; GO:0070402; F:NADPH binding; IEA:Ensembl.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0015936; P:coenzyme A metabolic process; IEA:InterPro.
DR GO; GO:0008299; P:isoprenoid biosynthetic process; IEA:InterPro.
DR GO; GO:1900222; P:negative regulation of amyloid-beta clearance; IEA:Ensembl.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IEA:Ensembl.
DR GO; GO:0050709; P:negative regulation of protein secretion; IEA:Ensembl.
DR GO; GO:0008542; P:visual learning; IEA:Ensembl.
DR CDD; cd00643; HMG-CoA_reductase_classI; 1.
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 Cholesterol biosynthesis; Cholesterol metabolism; Endoplasmic reticulum;
KW Glycoprotein; Isopeptide bond; Lipid biosynthesis; Lipid metabolism;
KW Membrane; NADP; Oxidoreductase; Peroxisome; Phosphoprotein;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..887
FT /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase"
FT /id="PRO_0000114418"
FT TOPO_DOM 1..9
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TRANSMEM 10..39
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TOPO_DOM 40..56
FT /note="Lumenal"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TRANSMEM 57..78
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TOPO_DOM 79..89
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TRANSMEM 90..114
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TOPO_DOM 115..123
FT /note="Lumenal"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TRANSMEM 124..149
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TOPO_DOM 150..159
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TRANSMEM 160..187
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TOPO_DOM 188..191
FT /note="Lumenal"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TRANSMEM 192..220
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TOPO_DOM 221..248
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:1374417"
FT TRANSMEM 249..275
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TOPO_DOM 276..314
FT /note="Lumenal"
FT /evidence="ECO:0000269|PubMed:1374417"
FT TRANSMEM 315..339
FT /note="Helical"
FT /evidence="ECO:0000305|PubMed:1374417"
FT TOPO_DOM 340..887
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:1374417"
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:0000250|UniProtKB:P04035"
FT ACT_SITE 558
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 690
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 766
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 865
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10003"
FT MOD_RES 871
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000269|PubMed:8415689"
FT CARBOHYD 281
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CROSSLNK 89
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:14563840,
FT ECO:0000269|PubMed:15247208"
FT CROSSLNK 248
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:14563840,
FT ECO:0000269|PubMed:15247208"
FT MUTAGEN 60
FT /note="S->N: Abolishes sterol-mediated interaction with
FT INSIG1, and no ubiquitination nor degradation."
FT /evidence="ECO:0000269|PubMed:17090658"
FT MUTAGEN 75
FT /note="Y->A: Very little effect on the sterol-mediated
FT ubiquitination and degradation of HMGCR. Marked reduction
FT in the sterol-mediated ubiquitination and degradation of
FT HMGCR; when associated with A-77. Completely abolishes the
FT sterol effect on ubiquitination and degradation of HMGCR;
FT when associated with A-76; A-77 and A-78."
FT /evidence="ECO:0000269|PubMed:14563840"
FT MUTAGEN 76
FT /note="I->A: Greatly reduced sterol-mediated ubiquitination
FT and degradation of HMGCR. Completely abolishes the sterol
FT effect on ubiquitination and degradation of HMGCR; when
FT associated with A-75; A-77 and A-78."
FT /evidence="ECO:0000269|PubMed:14563840"
FT MUTAGEN 77
FT /note="Y->A: Greatly reduced sterol-mediated ubiquitination
FT and degradation of HMGCR. Marked reduction in the sterol-
FT mediated ubiquitination and degradation of HMGCR; when
FT associated with A-75. Completely abolishes the sterol
FT effect on ubiquitination and degradation of HMGCR; when
FT associated with A-75; A-76 and A-78."
FT /evidence="ECO:0000269|PubMed:14563840"
FT MUTAGEN 78
FT /note="F->A: Very little effect on the sterol-mediated
FT ubiquitination and degradation of HMGCR. Completely
FT abolishes the sterol effect on ubiquitination and
FT degradation of HMGCR; when associated with A-75; A-76 and
FT A-77."
FT /evidence="ECO:0000269|PubMed:14563840"
FT MUTAGEN 87
FT /note="G->R: Abolishes sterol-mediated interaction with
FT INSIG1, and no ubiquitination nor degradation."
FT /evidence="ECO:0000269|PubMed:17090658"
FT MUTAGEN 89
FT /note="K->R: Little effect on sterol plus mevalonate-
FT stimulated ubiquitination and degradation of HMGCR in the
FT presence of INSIG1. No sterol plus mevalonate-stimulated
FT ubiquitination and degradation of HMGCR in the presence of
FT INSIG1; when associated with R-248."
FT /evidence="ECO:0000269|PubMed:14563840"
FT MUTAGEN 248
FT /note="K->R: Some reduction in sterol plus mevalonate-
FT stimulated ubiquitination and degradation of HMGCR in the
FT presence of INSIG1. No sterol plus mevalonate-stimulated
FT ubiquitination and degradation of HMGCR in the presence of
FT INSIG1; when associated with R-89."
FT /evidence="ECO:0000269|PubMed:14563840"
FT MUTAGEN 333
FT /note="A->P: Abolishes sterol-mediated interaction with
FT INSIG1, and no ubiquitination nor degradation."
FT /evidence="ECO:0000269|PubMed:17090658"
FT MUTAGEN 871
FT /note="S->A: Abolishes phosphorylation by AMPK. Blocks
FT inhibition of sterol synthesis induced by ATP depletion."
FT /evidence="ECO:0000269|PubMed:8415689"
SQ SEQUENCE 887 AA; 97081 MW; 4331E53ADA250E6A CRC64;
MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC PKFEEDVLSS
DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI FSSFVFSTVV IHFLDKELTG
LNEALPFFLL LIDLSRASAL AKFALSSNSQ DEVRENIARG MAILGPTFTL DALVECLVIG
VGTMSGVRQL EIMCCFGCMS VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR
VLEEEENKPN PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTTEHSKVS LGLDEDVSKR
IEPSVSLWQF YLSKMISMDI EQVVTLSLAF LLAVKYIFFE QAETESTLSL KNPITSPVVT
PKKAPDNCCR REPLLVRRSE KLSSVEEEPG VSQDRKVEVI KPLVVETESA SRATFVLGAS
GTSPPVAART QELEIELPSE PRPNEECLQI LESAEKGAKF LSDAEIIQLV NAKHIPAYKL
ETLMETHERG VSIRRQLLST KLPEPSSLQY LPYRDYNYSL VMGACCENVI GYMPIPVGVA
GPLCLDGKEY QVPMATTEGC LVASTNRGCR AIGLGGGASS RVLADGMTRG PVVRLPRACD
SAEVKAWLET PEGFAVIKDA FDSTSRFARL QKLHVTMAGR NLYIRFQSKT GDAMGMNMIS
KGTEKALLKL QEFFPEMQIL AVSGNYCTDK KPAAINWIEG RGKTVVCEAV IPAKVVREVL
KTTTEAMIDV NINKNLVGSA MAGSIGGYNA HAANIVTAIY IACGQDAAQN VGSSNCITLM
EASGPTNEDL YISCTMPSIE IGTVGGGTNL LPQQACLQML GVQGACKDNP GENARQLARI
VCGTVMAGEL SLMAALAAGH LVRSHMVHNR SKINLQDLQG TCTKKSA
