HMDH_RABIT
ID HMDH_RABIT Reviewed; 888 AA.
AC Q29512;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 25-MAY-2022, entry version 129.
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 Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE.
RC STRAIN=New Zealand white; TISSUE=Liver;
RA Yamada M., Yoshimatsu M., Kinowaki M., Kai M., Kondo K., Setoguchi T.;
RL Submitted (JUL-1996) 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. 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-872 reduces the catalytic
CC activity. {ECO:0000250|UniProtKB:P00347}.
CC -!- SIMILARITY: Belongs to the HMG-CoA reductase family. {ECO:0000305}.
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DR AlphaFoldDB; Q29512; -.
DR SMR; Q29512; -.
DR eggNOG; KOG2480; Eukaryota.
DR InParanoid; Q29512; -.
DR UniPathway; UPA00058; UER00103.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005778; C:peroxisomal membrane; ISS:UniProtKB.
DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IEA:UniProtKB-EC.
DR GO; GO:0050661; F:NADP binding; IEA:InterPro.
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 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 3: Inferred from homology;
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_0000114423"
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"
SQ SEQUENCE 888 AA; 97300 MW; 336CDEBF931110D9 CRC64;
MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN DKICGWNYEC PKFEEDVLSS
DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI FSSFVFSTVV IHFLDKELTG
LNEALPFFLL LIDLSRASAL AKFALSSNSQ DEVRENIARG MAILGPTFTL DALVECLVIG
VGTMSGVRQL EIMCCFGCMS VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR
VLEEEENKPN PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTADNSKVS LGLDENVSKR
IEPSVSLWQF YLSKMISMDI EQVITLSLAL LLAVKYIFFE QAETESTLSL KNPITSPVVT
QKKVPDSCCR REPVVVRNNQ KFCSVEEEAG MSQDRKVEVI KPLVAETDSP HRAAFVVGGS
SFPDTSLVLE TKEPEIELPK EPRPNEECLQ ILGNAEKGAK FLSDAEIIQL VNAKHIPAYK
LETLMETHER GVSIRRQLLS KKLPEPSSLQ YLPYRDYNYS LVLGACCENV IGYMPIPVGV
VGPLCLDGKE FQVPMATTEG CLVASTNRGC RAICLGGGAS SRVLADGMTR GPVVRLPRAC
DSAEVKAWLE TPEGFAVIKE AFDSTSRFAR LQKLHISMAG RNLYIRFQSR TGDAMGMNMI
SKGTEKALSK LHEYFPEMQI LAVSGNYCTD KKPAAVNWIE GRGKTVVCEA VIPAKVVREV
LKTTTEAMID VNINKNLVGS AMAGSIGGYN AHAANYVTAI YIACGQDAAQ NVGSSNCITL
MEASGPPNED LYISCTMPSI EIGTVGGGTN LLPQQACLQM LGVQGACKDS PGENARQLAR
IVCGTVMAGE LSLMAALAAG HLVKSHMIHN RSKINLQDLE GACTKKAA
