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 09-DEC-2015, entry version 189. DE RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase; DE Short=HMG-CoA reductase; DE EC=1.1.1.34; GN Name=HMGCR; 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] (ISOFORM 1). RX PubMed=2991281; RA Luskey K.L., Stevens B.; RT "Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved RT domains responsible for catalytic activity and sterol-regulated RT 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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., RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., RA 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP ENZYME REGULATION. RX PubMed=6995544; RA Brown M.S., Goldstein J.L.; RT "Multivalent feedback regulation of HMG CoA reductase, a control RT mechanism 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 RT insig-1 to its sterol-sensing domain."; RL Mol. Cell 11:25-33(2003). RN [9] 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 RT endoplasmic reticulum proteins, en route to proteasomal degradation."; RL Mol. Biol. Cell 20:3330-3341(2009). RN [10] 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 RT of 3-hydroxy-3-methylglutaryl-CoA reductase: evidence for requirement RT of a geranylgeranylated protein."; RL J. Biol. Chem. 286:32150-32161(2011). RN [11] RP TISSUE SPECIFICITY (ISOFORM 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) RT splice variant with an alternative exon 1 potentially encoding an RT extended N-terminus."; RL BMC Mol. Biol. 13:29-29(2012). RN [12] 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 RT cholesterol metabolic enzymes."; RL Hum. Mutat. 34:317-329(2013). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-872, AND IDENTIFICATION RP BY 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., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [14] 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 RT reductase: insights into regulation of activity and catalysis."; RL EMBO J. 19:819-830(2000). RN [15] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 426-888. 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 [16] 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., RA Dunbar J.B., Harris M.S., Hutchings R.H., Kennedy R.M., Larsen S.D., RA Pavlovsky A., Pfefferkorn J.A., Bainbridge G.; RT "Thermodynamic and structure guided design of statin based inhibitors RT of 3-hydroxy-3-methylglutaryl coenzyme A reductase."; RL J. Med. Chem. 51:3804-3813(2008). RN [17] 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 RT of human genes."; RL Nat. Genet. 22:231-238(1999). RN [18] RP ERRATUM. 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: Transmembrane glycoprotein that is the rate-limiting CC enzyme in cholesterol biosynthesis as well as in the biosynthesis CC of nonsterol isoprenoids that are essential for normal cell CC function including ubiquinone and geranylgeranyl proteins. CC -!- CATALYTIC ACTIVITY: (R)-mevalonate + CoA + 2 NADP(+) = (S)-3- CC hydroxy-3-methylglutaryl-CoA + 2 NADPH. {ECO:0000255|PROSITE- CC ProRule:PRU10003}. CC -!- ENZYME REGULATION: Regulated by a negative feedback mechanism CC through sterols and non-sterol metabolites derived from CC mevalonate. Inhibited by statins, a class of hypolipidemic agents CC used as pharmaceuticals to lower cholesterol levels in individuals CC at risk from cardiovascular disease due to hypercholesterolemia. CC Inhibition of HMGCR in the liver stimulates the LDL-receptors, CC which results in an increased clearance of LDL from the CC bloodstream and a decrease in blood cholesterol levels. The first CC results can be seen after one week of statin use and the effect is CC maximal after four to six weeks. {ECO:0000269|PubMed:6995544}. CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3. CC -!- SUBUNIT: Homodimer. Interacts (via its SSD) with INSIG1; the CC interaction, accelerated by sterols, leads to the recruitment of CC HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated CC ERAD pathway. Interacts with UBIAD1. {ECO:0000269|PubMed:10698924, CC ECO:0000269|PubMed:12535518, ECO:0000269|PubMed:18540668, CC ECO:0000269|PubMed:19458199, ECO:0000269|PubMed:23169578}. CC -!- INTERACTION: CC Q9Y5Z9:UBIAD1; NbExp=3; IntAct=EBI-465513, EBI-2819725; CC Q9Y5Z9-1:UBIAD1; NbExp=5; IntAct=EBI-465513, EBI-6621921; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass CC membrane protein. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P04035-1; Sequence=Displayed; CC Name=2; CC IsoId=P04035-2; Sequence=VSP_002207; CC Note=No experimental confirmation available.; CC Name=3; Synonyms=HMGCR-1b; CC IsoId=P04035-3; Sequence=VSP_046492; CC Note=Most highly expressed transcript in skin, esophagus, and CC uterine cervix.; 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-association CC degradation (ERAD). Accumulation of sterols in the endoplasmic CC reticulum (ER) membrane, triggers binding of the reductase to the CC ER membrane protein INSIG1. This INSIG1 binding leads to the CC recruitment of the ubiquitin ligase, AMFR/gp78, initiating CC ubiquitination of the reductase. The ubiquitinated reductase is CC then extracted from the ER membrane and delivered to cytosolic 26S CC proteosomes by a mechanism probably mediated by the ATPase CC Valosin-containing protein VCP/p97. Lys-248 is the main site of CC ubiquitination. Ubiquitination is enhanced by the presence of a CC geranylgeranylated protein. {ECO:0000269|PubMed:12535518, CC ECO:0000269|PubMed:19458199, ECO:0000269|PubMed:21778231}. CC -!- SIMILARITY: Belongs to the HMG-CoA reductase family. CC {ECO:0000305}. CC -!- SIMILARITY: Contains 1 SSD (sterol-sensing) domain. CC {ECO:0000255|PROSITE-ProRule:PRU00199}. CC -!- SEQUENCE CAUTION: CC Sequence=BAH12375.1; Type=Frameshift; Positions=122; 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 UniGene; Hs.628096; -. DR UniGene; Hs.643495; -. 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 ProteinModelPortal; P04035; -. DR SMR; P04035; 441-864. DR BioGrid; 109399; 31. DR IntAct; P04035; 3. DR STRING; 9606.ENSP00000287936; -. DR BindingDB; P04035; -. DR ChEMBL; CHEMBL402; -. DR DrugBank; DB01076; Atorvastatin. DR DrugBank; DB01095; Fluvastatin. DR DrugBank; DB00227; Lovastatin. DR DrugBank; DB08860; Pitavastatin. DR DrugBank; DB00175; Pravastatin. DR DrugBank; DB01098; Rosuvastatin. DR DrugBank; DB00641; Simvastatin. DR GuidetoPHARMACOLOGY; 639; -. DR SwissLipids; SLP:000001246; -. DR TCDB; 2.A.6.6.5; the resistance-nodulation-cell division (rnd) superfamily. DR PhosphoSite; P04035; -. DR BioMuta; HMGCR; -. DR DMDM; 123343; -. DR MaxQB; P04035; -. DR PaxDb; P04035; -. DR PRIDE; P04035; -. DR DNASU; 3156; -. DR Ensembl; ENST00000287936; ENSP00000287936; ENSG00000113161. [P04035-1] DR Ensembl; ENST00000343975; ENSP00000340816; ENSG00000113161. [P04035-2] DR Ensembl; ENST00000511206; ENSP00000426745; ENSG00000113161. [P04035-1] DR GeneID; 3156; -. DR KEGG; hsa:3156; -. DR UCSC; uc003kdp.3; human. [P04035-1] DR UCSC; uc003kdq.3; human. [P04035-2] DR CTD; 3156; -. DR GeneCards; HMGCR; -. DR HGNC; HGNC:5006; HMGCR. DR HPA; CAB016797; -. DR HPA; HPA008338; -. DR MIM; 142910; gene+phenotype. DR neXtProt; NX_P04035; -. DR PharmGKB; PA189; -. DR eggNOG; KOG2480; Eukaryota. DR eggNOG; COG1257; LUCA. DR GeneTree; ENSGT00800000124120; -. DR HOGENOM; HOG000183489; -. DR HOVERGEN; HBG000453; -. DR InParanoid; P04035; -. DR KO; K00021; -. DR OMA; PNEECLQ; -. DR OrthoDB; EOG7GXP9T; -. DR PhylomeDB; P04035; -. DR TreeFam; TF105362; -. DR BioCyc; MetaCyc:HS03652-MONOMER; -. DR BRENDA; 1.1.1.34; 2681. DR Reactome; R-HSA-191273; Cholesterol biosynthesis. DR Reactome; R-HSA-1989781; PPARA activates gene expression. DR Reactome; R-HSA-2426168; Activation of gene expression by SREBF (SREBP). DR SABIO-RK; P04035; -. DR UniPathway; UPA00058; UER00103. DR ChiTaRS; HMGCR; human. DR EvolutionaryTrace; P04035; -. DR GeneWiki; HMG-CoA_reductase; -. DR GenomeRNAi; 3156; -. DR NextBio; 12500; -. DR PRO; PR:P04035; -. DR Proteomes; UP000005640; Chromosome 5. DR Bgee; P04035; -. DR CleanEx; HS_HMGCR; -. 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; TAS:UniProtKB. DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW. DR GO; GO:0005622; C:intracellular; IBA:GO_Central. DR GO; GO:0005778; C:peroxisomal membrane; IDA:UniProtKB. DR GO; GO:0050662; F:coenzyme binding; IDA:UniProtKB. DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IBA:GO_Central. DR GO; GO:0042282; F:hydroxymethylglutaryl-CoA reductase activity; IDA:UniProtKB. DR GO; GO:0070402; F:NADPH binding; IDA:UniProtKB. DR GO; GO:0007568; P:aging; IEA:Ensembl. DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome. 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:0045445; P:myoblast differentiation; IEA:Ensembl. DR GO; GO:0061179; P:negative regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IEA:Ensembl. DR GO; GO:0010664; P:negative regulation of striated muscle cell apoptotic process; IEA:Ensembl. DR GO; GO:0045908; P:negative regulation of vasodilation; IEA:Ensembl. DR GO; GO:0061045; P:negative regulation of wound healing; IEA:Ensembl. DR GO; GO:0010666; P:positive regulation of cardiac muscle cell apoptotic process; IEA:Ensembl. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:0048643; P:positive regulation of skeletal muscle tissue development; IEA:Ensembl. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl. DR GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; IEA:Ensembl. DR GO; GO:0051262; P:protein tetramerization; IDA:UniProtKB. DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl. DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl. DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome. DR GO; GO:0006743; P:ubiquinone metabolic process; IEA:Ensembl. DR GO; GO:0008542; P:visual learning; IEA:Ensembl. DR Gene3D; 1.10.3270.10; -; 1. DR Gene3D; 3.30.70.420; -; 1. DR Gene3D; 3.90.770.10; -; 2. DR InterPro; IPR002202; HMG_CoA_Rdtase. DR InterPro; IPR023074; HMG_CoA_Rdtase_cat. 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_dom. DR InterPro; IPR009029; HMG_CoA_Rdtase_sub-bd_dom. DR InterPro; IPR000731; SSD. DR PANTHER; PTHR10572; PTHR10572; 1. DR Pfam; PF00368; HMG-CoA_red; 1. DR PRINTS; PR00071; HMGCOARDTASE. DR SUPFAM; SSF55035; SSF55035; 1. DR SUPFAM; SSF56542; SSF56542; 2. 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; Complete proteome; Endoplasmic reticulum; KW Glycoprotein; Isopeptide bond; Lipid biosynthesis; Lipid metabolism; KW Membrane; NADP; Oxidoreductase; Phosphoprotein; Polymorphism; KW Reference proteome; Steroid biosynthesis; Steroid metabolism; KW Sterol biosynthesis; Sterol metabolism; Transmembrane; KW Transmembrane helix; Ubl conjugation. FT CHAIN 1 888 3-hydroxy-3-methylglutaryl-coenzyme A FT reductase. FT /FTId=PRO_0000114419. FT TRANSMEM 10 39 Helical. {ECO:0000255}. FT TRANSMEM 57 78 Helical. {ECO:0000255}. FT TRANSMEM 90 114 Helical. {ECO:0000255}. FT TRANSMEM 124 149 Helical. {ECO:0000255}. FT TRANSMEM 160 187 Helical. {ECO:0000255}. FT TRANSMEM 192 220 Helical. {ECO:0000255}. FT TRANSMEM 315 339 Helical. {ECO:0000255}. FT DOMAIN 61 218 SSD. {ECO:0000255|PROSITE- FT ProRule:PRU00199}. FT REGION 340 449 Linker. FT REGION 450 888 Catalytic. FT MOTIF 75 78 INSIG-binding motif. FT COMPBIAS 243 246 Poly-Glu. FT ACT_SITE 559 559 Charge relay system. FT ACT_SITE 691 691 Charge relay system. FT ACT_SITE 767 767 Charge relay system. FT ACT_SITE 866 866 Proton donor. FT MOD_RES 872 872 Phosphoserine. FT {ECO:0000244|PubMed:24275569}. FT CARBOHYD 281 281 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 296 296 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 419 419 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 518 518 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 870 870 N-linked (GlcNAc...). {ECO:0000255}. FT CROSSLNK 89 89 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT {ECO:0000269|PubMed:19458199}. FT CROSSLNK 248 248 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin). FT {ECO:0000269|PubMed:19458199}. FT VAR_SEQ 1 1 M -> MQWMSHTRERDAGSKDSVATM (in isoform FT 3). {ECO:0000303|PubMed:14702039}. FT /FTId=VSP_046492. FT VAR_SEQ 522 574 Missing (in isoform 2). FT {ECO:0000303|PubMed:15489334}. FT /FTId=VSP_002207. FT VARIANT 638 638 I -> V (in dbSNP:rs5908). FT {ECO:0000269|PubMed:10391209}. FT /FTId=VAR_011954. FT MUTAGEN 75 77 YIY->AIA: Reduced sterol-mediated release FT from the ER. Not deglycosylated in FT response to sterols. FT {ECO:0000269|PubMed:19458199}. FT MUTAGEN 89 89 K->R: Abolishes sterol-mediated FT ubiquitination and degradation; when FT associated with R-248. FT {ECO:0000269|PubMed:19458199}. FT MUTAGEN 248 248 K->R: Abolishes sterol-mediated FT ubiquitination and degradation; when FT associated with R-89. FT {ECO:0000269|PubMed:19458199}. FT HELIX 445 453 {ECO:0000244|PDB:2R4F}. FT TURN 455 457 {ECO:0000244|PDB:2R4F}. FT HELIX 458 460 {ECO:0000244|PDB:2R4F}. FT HELIX 464 472 {ECO:0000244|PDB:2R4F}. FT STRAND 474 476 {ECO:0000244|PDB:3CDA}. FT HELIX 478 480 {ECO:0000244|PDB:2R4F}. FT HELIX 481 484 {ECO:0000244|PDB:2R4F}. FT STRAND 485 487 {ECO:0000244|PDB:2R4F}. FT HELIX 488 502 {ECO:0000244|PDB:2R4F}. FT STRAND 503 505 {ECO:0000244|PDB:2R4F}. FT HELIX 508 511 {ECO:0000244|PDB:2R4F}. FT STRAND 515 517 {ECO:0000244|PDB:1DQ9}. FT HELIX 519 521 {ECO:0000244|PDB:2R4F}. FT TURN 522 525 {ECO:0000244|PDB:2R4F}. FT STRAND 528 546 {ECO:0000244|PDB:2R4F}. FT STRAND 549 556 {ECO:0000244|PDB:2R4F}. FT HELIX 562 575 {ECO:0000244|PDB:2R4F}. FT STRAND 579 590 {ECO:0000244|PDB:2R4F}. FT STRAND 593 595 {ECO:0000244|PDB:2R4F}. FT HELIX 599 610 {ECO:0000244|PDB:2R4F}. FT HELIX 612 623 {ECO:0000244|PDB:2R4F}. FT STRAND 635 639 {ECO:0000244|PDB:2R4F}. FT STRAND 642 650 {ECO:0000244|PDB:2R4F}. FT HELIX 657 674 {ECO:0000244|PDB:2R4F}. FT STRAND 679 683 {ECO:0000244|PDB:2R4F}. FT STRAND 686 688 {ECO:0000244|PDB:1DQA}. FT HELIX 695 700 {ECO:0000244|PDB:2R4F}. FT STRAND 703 712 {ECO:0000244|PDB:2R4F}. FT HELIX 714 719 {ECO:0000244|PDB:2R4F}. FT STRAND 721 723 {ECO:0000244|PDB:2R4F}. FT HELIX 725 736 {ECO:0000244|PDB:2R4F}. FT HELIX 738 742 {ECO:0000244|PDB:2R4F}. FT STRAND 746 752 {ECO:0000244|PDB:2R4F}. FT HELIX 753 763 {ECO:0000244|PDB:2R4F}. FT HELIX 768 770 {ECO:0000244|PDB:2R4F}. FT HELIX 771 774 {ECO:0000244|PDB:2R4F}. FT STRAND 777 785 {ECO:0000244|PDB:2R4F}. FT STRAND 790 800 {ECO:0000244|PDB:2R4F}. FT STRAND 804 806 {ECO:0000244|PDB:2R4F}. FT HELIX 807 810 {ECO:0000244|PDB:2R4F}. FT HELIX 812 820 {ECO:0000244|PDB:2R4F}. FT STRAND 828 830 {ECO:0000244|PDB:2R4F}. FT HELIX 833 859 {ECO:0000244|PDB:2R4F}. FT HELIX 862 869 {ECO:0000244|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 //