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 27-MAR-2024, entry version 190. 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}. 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; 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; 3. DR STRING; 10090.ENSMUSP00000022176; -. DR BindingDB; Q01237; -. DR ChEMBL; CHEMBL2764; -. DR DrugCentral; Q01237; -. DR GuidetoPHARMACOLOGY; 639; -. DR GlyCosmos; Q01237; 1 site, No reported glycans. DR GlyGen; Q01237; 1 site. DR iPTMnet; Q01237; -. DR PhosphoSitePlus; Q01237; -. DR EPD; Q01237; -. DR jPOST; Q01237; -. DR MaxQB; Q01237; -. DR PaxDb; 10090-ENSMUSP00000022176; -. DR PeptideAtlas; Q01237; -. DR ProteomicsDB; 267050; -. DR Pumba; Q01237; -. DR Antibodypedia; 24380; 469 antibodies from 35 providers. DR DNASU; 15357; -. DR Ensembl; ENSMUST00000022176.15; ENSMUSP00000022176.9; ENSMUSG00000021670.15. DR GeneID; 15357; -. DR KEGG; mmu:15357; -. DR UCSC; uc007rnm.3; mouse. DR AGR; MGI:96159; -. 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; DCHIAMD; -. DR OrthoDB; 816560at2759; -. 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 83 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 266 other cell types or tissues. DR ExpressionAtlas; Q01237; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central. DR GO; GO:0005778; C:peroxisomal membrane; ISS:UniProtKB. DR GO; GO:0120225; F:coenzyme A binding; ISO:MGI. DR GO; GO:0030695; F:GTPase regulator activity; IGI: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:0060291; P:long-term synaptic potentiation; IGI:MGI. 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: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: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:0070372; P:regulation of ERK1 and ERK2 cascade; IGI: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; HMGR, N-terminal domain; 1. DR Gene3D; 3.30.70.420; Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain; 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 NCBIfam; TIGR00920; 2A060605; 1. DR NCBIfam; TIGR00533; HMG_CoA_R_NADP; 1. DR PANTHER; PTHR10572; 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A REDUCTASE; 1. DR PANTHER; PTHR10572:SF24; 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A REDUCTASE; 1. DR Pfam; PF00368; HMG-CoA_red; 1. DR Pfam; PF12349; Sterol-sensing; 1. DR PRINTS; PR00071; HMGCOARDTASE. DR SUPFAM; SSF82866; Multidrug efflux transporter AcrB transmembrane domain; 1. DR SUPFAM; SSF55035; NAD-binding domain of HMG-CoA reductase; 1. DR SUPFAM; SSF56542; Substrate-binding domain of HMG-CoA reductase; 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. DR Genevisible; Q01237; MM. 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 //