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Protein

3-hydroxy-3-methylglutaryl-coenzyme A reductase

Gene

HMGCR

Organism
Mesocricetus auratus (Golden hamster)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins.

Catalytic activityi

(R)-mevalonate + CoA + 2 NADP+ = (S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADPH.PROSITE-ProRule annotation

Enzyme regulationi

Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate.

Pathwayi: (R)-mevalonate biosynthesis

This protein is involved in step 3 of the subpathway that synthesizes (R)-mevalonate from acetyl-CoA.
Proteins known to be involved in the 3 steps of the subpathway in this organism are:
  1. no protein annotated in this organism
  2. no protein annotated in this organism
  3. 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)
This subpathway is part of the pathway (R)-mevalonate biosynthesis, which is itself part of Metabolic intermediate biosynthesis.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes (R)-mevalonate from acetyl-CoA, the pathway (R)-mevalonate biosynthesis and in Metabolic intermediate biosynthesis.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei558 – 5581Charge relay systemBy similarity
Active sitei690 – 6901Charge relay systemBy similarity
Active sitei766 – 7661Charge relay systemBy similarity
Active sitei865 – 8651Proton donorPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Keywords - Biological processi

Cholesterol biosynthesis, Cholesterol metabolism, Lipid biosynthesis, Lipid metabolism, Steroid biosynthesis, Steroid metabolism, Sterol biosynthesis, Sterol metabolism

Keywords - Ligandi

NADP

Enzyme and pathway databases

SABIO-RKP09610.
UniPathwayiUPA00058; UER00103.

Names & Taxonomyi

Protein namesi
Recommended name:
3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC:1.1.1.34)
Short name:
HMG-CoA reductase
Gene namesi
Name:HMGCR
OrganismiMesocricetus auratus (Golden hamster)
Taxonomic identifieri10036 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaCricetidaeCricetinaeMesocricetus

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei10 – 3930HelicalSequence analysisAdd
BLAST
Transmembranei57 – 7822HelicalSequence analysisAdd
BLAST
Transmembranei90 – 11425HelicalSequence analysisAdd
BLAST
Transmembranei124 – 14926HelicalSequence analysisAdd
BLAST
Transmembranei160 – 18728HelicalSequence analysisAdd
BLAST
Transmembranei192 – 22029HelicalSequence analysisAdd
BLAST
Transmembranei315 – 33925HelicalSequence analysisAdd
BLAST

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi474 – 4741H → Q: No loss of activity. 1 Publication
Mutagenesisi487 – 4871H → Q: No loss of activity. 1 Publication
Mutagenesisi558 – 5581E → D or Q: Loss of activity. 1 Publication
Mutagenesisi751 – 7511H → Q: No loss of activity. 1 Publication
Mutagenesisi766 – 7661D → N: Loss of activity. 1 Publication
Mutagenesisi860 – 8601H → Q: No loss of activity. 1 Publication
Mutagenesisi865 – 8651H → K or Q: Loss of activity. 1 Publication
Mutagenesisi868 – 8681H → Y: No loss of activity. 1 Publication

Chemistry

ChEMBLiCHEMBL1075267.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 8878873-hydroxy-3-methylglutaryl-coenzyme A reductasePRO_0000114420Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Cross-linki89 – 89Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki248 – 248Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Glycosylationi281 – 2811N-linked (GlcNAc...)Sequence analysis
Glycosylationi517 – 5171N-linked (GlcNAc...)Sequence analysis
Glycosylationi869 – 8691N-linked (GlcNAc...)Sequence analysis
Modified residuei871 – 8711Phosphoserine; by AMPKBy similarity

Post-translational modificationi

N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.By similarity
Undergoes sterol-mediated ubiquitination and ER-association degradation (ERAD). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1. This INSIG binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, initiating ubiquitination of the reductase. The ubiquitinated reductase is then extracted from the ER membrane and delivered to cytosolic 26S proteosomes by a mechanism probably mediated by the ATPase Valosin-containing protein VCP/p97. Lys-248 is the main site of ubiquitination. Ubiquitination is enhanced by the presence of a geranylgeranylated protein (By similarity).By similarity

Keywords - PTMi

Glycoprotein, Isopeptide bond, Phosphoprotein, Ubl conjugation

PTM databases

iPTMnetiP09610.

Interactioni

Subunit structurei

Homodimer. Interacts with INSIG1 (via its SSD); the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway. Interacts with UBIAD1 (By similarity).By similarity

Chemistry

BindingDBiP09610.

Structurei

3D structure databases

ProteinModelPortaliP09610.
SMRiP09610. Positions 440-864.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini61 – 218158SSDPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni340 – 449110LinkerAdd
BLAST
Regioni450 – 887438CatalyticAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi75 – 784INSIG-binding motifBy similarity

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi243 – 2464Poly-Glu

Sequence similaritiesi

Belongs to the HMG-CoA reductase family.Curated
Contains 1 SSD (sterol-sensing) domain.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

HOVERGENiHBG000453.

Family and domain databases

Gene3Di1.10.3270.10. 1 hit.
3.30.70.420. 1 hit.
3.90.770.10. 2 hits.
InterProiIPR002202. HMG_CoA_Rdtase.
IPR023074. HMG_CoA_Rdtase_cat.
IPR023076. HMG_CoA_Rdtase_CS.
IPR004554. HMG_CoA_Rdtase_eu_arc.
IPR004816. HMG_CoA_Rdtase_metazoan.
IPR023282. HMG_CoA_Rdtase_N.
IPR009023. HMG_CoA_Rdtase_NAD(P)-bd_dom.
IPR009029. HMG_CoA_Rdtase_sub-bd_dom.
IPR000731. SSD.
[Graphical view]
PANTHERiPTHR10572. PTHR10572. 1 hit.
PfamiPF00368. HMG-CoA_red. 1 hit.
PF12349. Sterol-sensing. 1 hit.
[Graphical view]
PRINTSiPR00071. HMGCOARDTASE.
SUPFAMiSSF55035. SSF55035. 1 hit.
SSF56542. SSF56542. 2 hits.
TIGRFAMsiTIGR00920. 2A060605. 1 hit.
TIGR00533. HMG_CoA_R_NADP. 1 hit.
PROSITEiPS00066. HMG_COA_REDUCTASE_1. 1 hit.
PS00318. HMG_COA_REDUCTASE_2. 1 hit.
PS01192. HMG_COA_REDUCTASE_3. 1 hit.
PS50065. HMG_COA_REDUCTASE_4. 1 hit.
PS50156. SSD. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P09610-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC
60 70 80 90 100
PKFEEDVLSS DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI
110 120 130 140 150
FSSFVFSTVV IHFLDKELTG LNEALPFFLL LIDLSRASAL AKFALSSNSQ
160 170 180 190 200
DEVRENIARG MAILGPTFTL DALVECLVIG VGTMSGVRQL EIMCCFGCMS
210 220 230 240 250
VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR VLEEEENKPN
260 270 280 290 300
PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTTEHSKVS LGLDEDVSKR
310 320 330 340 350
IEPSVSLWQF YLSKMISMDI EQVVTLSLAF LLAVKYIFFE QAETESTLSL
360 370 380 390 400
KNPITSPVAT PKKAPDNCCR REPVLSRRNE KLSSVEEEPG VNQDRKVEVI
410 420 430 440 450
KPLVAETEST SRATFVLGAS GGCSPVALGT QEPEIELPSE PRPNEECLQI
460 470 480 490 500
LESAEKGAKF LSDAEIIQLV NAKHIPAYKL ETLMETHERG VSIRRQLLST
510 520 530 540 550
KLPEPSSLQY LPYRDYNYSL VMGACCENVI GYMPIPVGVA GPLCLDGKEY
560 570 580 590 600
QVPMATTEGC LVASTNRGCR AIGLGGGASS RVLADGMTRG PVVRLPRACD
610 620 630 640 650
SAEVKAWLET PEGFAVIKDA FDSTSRFARL QKLHVTMAGR NLYIRFQSKT
660 670 680 690 700
GDAMGMNMIS KGTEKALVKL QEFFPEMQIL AVSGNYCTDK KPAAVNWIEG
710 720 730 740 750
RGKTVVCEAV IPARVVREVL KTTTEAMIDV NINKNLVGSA MAGSIGGYNA
760 770 780 790 800
HAANIVTAIY IACGQDAAQN VGSSNCITLM EASGPTNEDL YISCTMPSIE
810 820 830 840 850
IGTVGGGTNL LPQQACLQML GVQGACKDNP GENARQLARI VCGTVMAGEL
860 870 880
SLMAALAAGH LVRSHMVHNR SKINLQDLQG TCTKKAA
Length:887
Mass (Da):96,955
Last modified:July 1, 1989 - v1
Checksum:iBC6F9D1F8CAD5EA5
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M12705 mRNA. Translation: AAA37077.1.
PIRiA23586.
RefSeqiNP_001268631.1. NM_001281702.1.

Genome annotation databases

GeneIDi101843185.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M12705 mRNA. Translation: AAA37077.1.
PIRiA23586.
RefSeqiNP_001268631.1. NM_001281702.1.

3D structure databases

ProteinModelPortaliP09610.
SMRiP09610. Positions 440-864.
ModBaseiSearch...
MobiDBiSearch...

Chemistry

BindingDBiP09610.
ChEMBLiCHEMBL1075267.

PTM databases

iPTMnetiP09610.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi101843185.

Organism-specific databases

CTDi3156.

Phylogenomic databases

HOVERGENiHBG000453.

Enzyme and pathway databases

UniPathwayiUPA00058; UER00103.
SABIO-RKP09610.

Miscellaneous databases

PROiP09610.

Family and domain databases

Gene3Di1.10.3270.10. 1 hit.
3.30.70.420. 1 hit.
3.90.770.10. 2 hits.
InterProiIPR002202. HMG_CoA_Rdtase.
IPR023074. HMG_CoA_Rdtase_cat.
IPR023076. HMG_CoA_Rdtase_CS.
IPR004554. HMG_CoA_Rdtase_eu_arc.
IPR004816. HMG_CoA_Rdtase_metazoan.
IPR023282. HMG_CoA_Rdtase_N.
IPR009023. HMG_CoA_Rdtase_NAD(P)-bd_dom.
IPR009029. HMG_CoA_Rdtase_sub-bd_dom.
IPR000731. SSD.
[Graphical view]
PANTHERiPTHR10572. PTHR10572. 1 hit.
PfamiPF00368. HMG-CoA_red. 1 hit.
PF12349. Sterol-sensing. 1 hit.
[Graphical view]
PRINTSiPR00071. HMGCOARDTASE.
SUPFAMiSSF55035. SSF55035. 1 hit.
SSF56542. SSF56542. 2 hits.
TIGRFAMsiTIGR00920. 2A060605. 1 hit.
TIGR00533. HMG_CoA_R_NADP. 1 hit.
PROSITEiPS00066. HMG_COA_REDUCTASE_1. 1 hit.
PS00318. HMG_COA_REDUCTASE_2. 1 hit.
PS01192. HMG_COA_REDUCTASE_3. 1 hit.
PS50065. HMG_COA_REDUCTASE_4. 1 hit.
PS50156. SSD. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "The nucleotide sequence of Syrian hamster HMG-CoA reductase cDNA."
    Skalnik D.G., Simoni R.D.
    DNA 4:439-444(1985) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  2. "His865 is the catalytically important histidyl residue of Syrian hamster 3-hydroxy-3-methylglutaryl-coenzyme A reductase."
    Darnay B.G., Rodwell V.W.
    J. Biol. Chem. 268:8429-8435(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACTIVE SITES, MUTAGENESIS OF HIS-474; HIS-487; HIS-751; HIS-860; HIS-865 AND HIS-868.
  3. "The active site of hamster 3-hydroxy-3-methylglutaryl-CoA reductase resides at the subunit interface and incorporates catalytically essential acidic residues from separate polypeptides."
    Frimpong K., Rodwell V.W.
    J. Biol. Chem. 269:1217-1221(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACTIVE SITES, SUBUNIT, MUTAGENESIS OF GLU-558 AND ASP-766.

Entry informationi

Entry nameiHMDH_MESAU
AccessioniPrimary (citable) accession number: P09610
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 1, 1989
Last sequence update: July 1, 1989
Last modified: June 8, 2016
This is version 118 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Documents

  1. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.