HMDH_BOVIN
ID HMDH_BOVIN Reviewed; 888 AA.
AC A7Z064; F1MMP6;
DT 13-JUN-2012, integrated into UniProtKB/Swiss-Prot.
DT 13-JUN-2012, sequence version 2.
DT 03-AUG-2022, entry version 100.
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 Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Hereford;
RX PubMed=19393038; DOI=10.1186/gb-2009-10-4-r42;
RA Zimin A.V., Delcher A.L., Florea L., Kelley D.R., Schatz M.C., Puiu D.,
RA Hanrahan F., Pertea G., Van Tassell C.P., Sonstegard T.S., Marcais G.,
RA Roberts M., Subramanian P., Yorke J.A., Salzberg S.L.;
RT "A whole-genome assembly of the domestic cow, Bos taurus.";
RL Genome Biol. 10:R42.01-R42.10(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Hereford; TISSUE=Hippocampus;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (SEP-2007) to the EMBL/GenBank/DDBJ databases.
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-872 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 (By similarity). Interacts (via its
CC SSD) with INSIG1; the interaction, accelerated by sterols, leads to the
CC recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-
CC mediated ERAD pathway. Interacts with UBIAD1 (By similarity).
CC {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-872 reduces the catalytic
CC activity. {ECO:0000250|UniProtKB:P00347}.
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; DAAA02027738; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC153262; AAI53263.1; -; mRNA.
DR RefSeq; NP_001099083.1; NM_001105613.1.
DR AlphaFoldDB; A7Z064; -.
DR SMR; A7Z064; -.
DR STRING; 9913.ENSBTAP00000010315; -.
DR PaxDb; A7Z064; -.
DR PRIDE; A7Z064; -.
DR Ensembl; ENSBTAT00000010315; ENSBTAP00000010315; ENSBTAG00000007840.
DR GeneID; 407159; -.
DR KEGG; bta:407159; -.
DR CTD; 3156; -.
DR VEuPathDB; HostDB:ENSBTAG00000007840; -.
DR VGNC; VGNC:29879; HMGCR.
DR eggNOG; KOG2480; Eukaryota.
DR GeneTree; ENSGT00940000155305; -.
DR HOGENOM; CLU_001734_0_1_1; -.
DR InParanoid; A7Z064; -.
DR OMA; CHGWSQS; -.
DR OrthoDB; 907394at2759; -.
DR TreeFam; TF105362; -.
DR Reactome; R-BTA-191273; Cholesterol biosynthesis.
DR UniPathway; UPA00058; UER00103.
DR Proteomes; UP000009136; Chromosome 10.
DR Bgee; ENSBTAG00000007840; Expressed in diaphragm and 103 other tissues.
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: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; IBA:GO_Central.
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; IBA:GO_Central.
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: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 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 2: Evidence at transcript 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..888
FT /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase"
FT /id="PRO_0000417950"
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:0000250|UniProtKB:P04035"
FT ACT_SITE 559
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 691
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 767
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 866
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10003"
FT MOD_RES 872
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:P51639"
FT CARBOHYD 281
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 296
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 628
FT /note="F -> V (in Ref. 2; AAI53263)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 888 AA; 97727 MW; 16CFA777C3AA9D1A CRC64;
MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC PKLEEDVLSS
DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI FSSFVFSTVV IHFLDKELTG
LNEALPFFLL LVDLSRASAL AKFALSSNSQ DEVRENIARG MAILGPTFTL DALVECLVIG
VGTMSGVRQL EIMCCFGCMS VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR
VLEEEENKPN PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTADNSKVS LGLDENVSKR
IEPSVSLWQF YLSKMISMDI EQVITLSLAL LLAVKYIFFE QAETESTLSL KNPITSPVVT
QKKITDDCCR RDPVLVRNDQ KFHAMEEETR KNRERKVEVI KPLLAENDTS HRATFVVGNS
SLLGTSLELE TQEPEMELPV EPRPNEECLQ ILENAEKGAK FLSDAEIIQL VNAKHIPAYK
LETLMETHER GVSIRRQLLS KKLPEPSSLQ YLPYRDYNYS LVMGACCENV IGYMPIPVGV
AGPLCLDGKE FQVPMATTEG CLVASTNRGC RAIGLGGGAS SRVLADGMTR GPVVRFPRAC
DSAEVKAWLE TPEGFTVIKE AFDSTSRFAR LQKLHMSVAG RNLYIRFQSR SGDAMGMNMI
SKGTEKALSK LQEYFPEMQI LAVSGNYCTD KKPAAINWIE GRGKSVVCEA VIPAKVVREV
LKTTTEAMIE VNINKNLVGS AMAGSIGGYN AHAANIVTAI YIACGQDAAQ NVGSSNCITL
MEASGPTNED LYISCTMPSI EIGTVGGGTN LLPQQACLQM LGVQGACRDN PGENARQLAR
IVCGTVMAGE LSLMAALAAG HLVRSHMIHN RSKINLQDLQ GTCTKKAA
