HMDH_MOUSE
ID HMDH_MOUSE Reviewed; 887 AA.
AC Q01237; G3X8U5; Q5U4I2;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2012, sequence version 3.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase;
DE Short=HMG-CoA reductase;
DE EC=1.1.1.34 {ECO:0000269|PubMed:16100574};
GN Name=Hmgcr;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Mammary tumor;
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 664-887.
RX PubMed=2258621;
RA Helmberg A., Faessler R., Geley S., Joehrer K., Kroemer G., Boeck G.,
RA Kofler R.;
RT "Glucocorticoid-regulated gene expression in the immune system. Analysis of
RT glucocorticoid-regulated transcripts from the mouse macrophage-like cell
RT line P388D1.";
RL J. Immunol. 145:4332-4337(1990).
RN [5]
RP DISRUPTION PHENOTYPE.
RX PubMed=12920113; DOI=10.1074/jbc.m307228200;
RA Ohashi K., Osuga J., Tozawa R., Kitamine T., Yagyu H., Sekiya M.,
RA Tomita S., Okazaki H., Tamura Y., Yahagi N., Iizuka Y., Harada K.,
RA Gotoda T., Shimano H., Yamada N., Ishibashi S.;
RT "Early embryonic lethality caused by targeted disruption of the 3-hydroxy-
RT 3-methylglutaryl-CoA reductase gene.";
RL J. Biol. Chem. 278:42936-42941(2003).
RN [6]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=16100574; DOI=10.1172/jci25614;
RA Engelking L.J., Liang G., Hammer R.E., Takaishi K., Kuriyama H.,
RA Evers B.M., Li W.P., Horton J.D., Goldstein J.L., Brown M.S.;
RT "Schoenheimer effect explained--feedback regulation of cholesterol
RT synthesis in mice mediated by Insig proteins.";
RL J. Clin. Invest. 115:2489-2498(2005).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-871, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
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:0000269|PubMed:16100574}.
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:16100574};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15991;
CC Evidence={ECO:0000305|PubMed:16100574};
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 (By similarity). {ECO:0000250|UniProtKB:P00347,
CC ECO:0000250|UniProtKB:P04035}.
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. Interacts with UBIAD1. {ECO:0000250|UniProtKB:P04035}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P04035}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P00347}. Peroxisome membrane
CC {ECO:0000250|UniProtKB:P04035}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P00347}.
CC -!- PTM: Undergoes sterol-mediated ubiquitination and ER-associated
CC degradation (ERAD). Accumulation of sterols in the endoplasmic
CC reticulum (ER) membrane, triggers binding of the reductase to the ER
CC membrane protein INSIG1 or INSIG2. The INSIG1 binding leads to the
CC recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145,
CC initiating ubiquitination of the reductase. The ubiquitinated reductase
CC is then 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. The INSIG2-binding leads to the recruitment
CC of the ubiquitin ligase RNF139, initiating ubiquitination of the
CC reductase. Lys-248 is the main site of ubiquitination. Ubiquitination
CC is enhanced by the presence of a geranylgeranylated protein.
CC {ECO:0000250|UniProtKB:P04035}.
CC -!- PTM: N-glycosylated. Deglycosylated by NGLY1 on release from the
CC endoplasmic reticulum (ER) in a sterol-mediated manner.
CC {ECO:0000250|UniProtKB:P04035}.
CC -!- PTM: Phosphorylated. Phosphorylation at Ser-871 reduces the catalytic
CC activity. {ECO:0000250|UniProtKB:P00347}.
CC -!- DISRUPTION PHENOTYPE: Homozygous knockout mice show early embryonic
CC lethality. {ECO:0000269|PubMed:12920113}.
CC -!- SIMILARITY: Belongs to the HMG-CoA reductase family. {ECO:0000305}.
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DR EMBL; AC154851; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466567; EDL00884.1; -; Genomic_DNA.
DR EMBL; BC085083; AAH85083.1; -; mRNA.
DR EMBL; M62766; AAA37819.1; -; mRNA.
DR CCDS; CCDS26706.1; -.
DR PIR; A43533; A43533.
DR RefSeq; NP_032281.2; NM_008255.2.
DR RefSeq; XP_006517594.1; XM_006517531.1.
DR AlphaFoldDB; Q01237; -.
DR SMR; Q01237; -.
DR BioGRID; 200338; 2.
DR STRING; 10090.ENSMUSP00000022176; -.
DR BindingDB; Q01237; -.
DR ChEMBL; CHEMBL2764; -.
DR DrugCentral; Q01237; -.
DR GuidetoPHARMACOLOGY; 639; -.
DR GlyGen; Q01237; 1 site.
DR iPTMnet; Q01237; -.
DR PhosphoSitePlus; Q01237; -.
DR EPD; Q01237; -.
DR jPOST; Q01237; -.
DR MaxQB; Q01237; -.
DR PaxDb; Q01237; -.
DR PeptideAtlas; Q01237; -.
DR PRIDE; Q01237; -.
DR ProteomicsDB; 267050; -.
DR Antibodypedia; 24380; 358 antibodies from 35 providers.
DR DNASU; 15357; -.
DR Ensembl; ENSMUST00000022176; ENSMUSP00000022176; ENSMUSG00000021670.
DR GeneID; 15357; -.
DR KEGG; mmu:15357; -.
DR UCSC; uc007rnm.3; mouse.
DR CTD; 3156; -.
DR MGI; MGI:96159; Hmgcr.
DR VEuPathDB; HostDB:ENSMUSG00000021670; -.
DR eggNOG; KOG2480; Eukaryota.
DR GeneTree; ENSGT00940000155305; -.
DR HOGENOM; CLU_001734_0_1_1; -.
DR InParanoid; Q01237; -.
DR OMA; CHGWSQS; -.
DR OrthoDB; 907394at2759; -.
DR PhylomeDB; Q01237; -.
DR TreeFam; TF105362; -.
DR BRENDA; 1.1.1.34; 3474.
DR Reactome; R-MMU-191273; Cholesterol biosynthesis.
DR SABIO-RK; Q01237; -.
DR UniPathway; UPA00058; UER00103.
DR BioGRID-ORCS; 15357; 17 hits in 78 CRISPR screens.
DR ChiTaRS; Hmgcr; mouse.
DR PRO; PR:Q01237; -.
DR Proteomes; UP000000589; Chromosome 13.
DR RNAct; Q01237; protein.
DR Bgee; ENSMUSG00000021670; Expressed in spermatocyte and 263 other tissues.
DR ExpressionAtlas; Q01237; baseline and differential.
DR Genevisible; Q01237; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS: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:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005778; C:peroxisomal membrane; ISS:UniProtKB.
DR GO; GO:0120225; F:coenzyme A binding; ISO:MGI.
DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IDA:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0070402; F:NADPH binding; ISO:MGI.
DR GO; GO:0051721; F:protein phosphatase 2A binding; ISO:MGI.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IDA:MGI.
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; IMP:ARUK-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:MGI.
DR GO; GO:0061179; P:negative regulation of insulin secretion involved in cellular response to glucose stimulus; ISO:MGI.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IGI:MGI.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IMP:ARUK-UCL.
DR GO; GO:0050709; P:negative regulation of protein secretion; IMP:ARUK-UCL.
DR GO; GO:0010664; P:negative regulation of striated muscle cell apoptotic process; ISO:MGI.
DR GO; GO:0061045; P:negative regulation of wound healing; ISO:MGI.
DR GO; GO:0010666; P:positive regulation of cardiac muscle cell apoptotic process; ISO:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISO:MGI.
DR GO; GO:0048643; P:positive regulation of skeletal muscle tissue development; ISO:MGI.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISO:MGI.
DR GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; ISO:MGI.
DR GO; GO:0045907; P:positive regulation of vasoconstriction; ISO:MGI.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR GO; GO:0006743; P:ubiquinone metabolic process; ISO:MGI.
DR GO; GO:0008542; P:visual learning; IGI:MGI.
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 Reference proteome; Steroid biosynthesis; Steroid metabolism;
KW Sterol biosynthesis; Sterol metabolism; Transmembrane; Transmembrane helix;
KW Ubl conjugation.
FT CHAIN 1..887
FT /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase"
FT /id="PRO_0000114421"
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..887
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: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"
FT /evidence="ECO:0007744|PubMed:21183079"
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:0000250|UniProtKB:P00347"
FT CROSSLNK 248
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P00347"
FT CONFLICT 258
FT /note="M -> I (in Ref. 3; AAH85083)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 887 AA; 97040 MW; DD77B40CE66ABF92 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 NSTAEQAKVS LGLDEDVSKR
IEPSVSLWQF YLSKMISMDI EQVITLSLAF LLAVKYIFFE QAETESTLSL KNPITSPVVT
SKKAQDNCCR REPLLVRRNQ KLSSVEEDPG ANQERKVEVI KPLVVEAETT SRATFVLGAS
VASPPSALGT QEPGIELPIE PRPNEECLQI LENAEKGAKF LSDAEIIQLV NAKHIPAYKL
ETLMETHERG VSIRRQLLST KLAEPSSLQY LPYRDYNYSL VMGACCENVI GYMPIPVGVA
GPLCLDGKEY QVPMATTEGC LVASTNRGCR AISLGGGASS RVLADGMTRG PVVRLPRACD
SAEVKTWLET PEGFAVIKEA FDSTSRFARL QKLHVTMAGR NLYIRFQSRT GDAMGMNMIS
KGTEKALLKL QEFFPDMQIL AVSGNYCTDK KPAAINWIEG RGKTVVCEAV IPAKVVREVL
KTTTEAMVDV NINKNLVGSA MAGSIGGYNA HAANIVTAIY IACGQDAAQN VGSSNCITLM
EASGPTNEDL YISCTMPSIE IGTVGGGTNL LPQQACLQML GVQGACKDNP GENARQLARI
VCGTVMAGEL SLMAALAAGH LVRSHMVHNR SKINLQDLQG TCTKKAA
