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Protein

3-hydroxy-3-methylglutaryl-coenzyme A reductase

Gene

HMGCR

Organism
Mesocricetus auratus (Golden hamster)
Status
Reviewed-Annotation score: -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. 3-hydroxy-3-methylglutaryl coenzyme A synthase (Hmgcs2), 3-hydroxy-3-methylglutaryl coenzyme A synthase (Hmgcs1), 3-hydroxy-3-methylglutaryl coenzyme A synthase
  3. 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr), 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr), 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)DescriptionActionsGraphical viewLength
Active sitei558Charge relay systemBy similarity1
Active sitei690Charge relay systemBy similarity1
Active sitei766Charge relay systemBy similarity1
Active sitei865Proton donorPROSITE-ProRule annotation1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionOxidoreductase
Biological processCholesterol biosynthesis, Cholesterol metabolism, Lipid biosynthesis, Lipid metabolism, Steroid biosynthesis, Steroid metabolism, Sterol biosynthesis, Sterol metabolism
LigandNADP

Enzyme and pathway databases

SABIO-RKiP09610
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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaCricetidaeCricetinaeMesocricetus
Proteomesi
  • UP000189706 Componenti: Genome assembly

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transmembranei10 – 39HelicalSequence analysisAdd BLAST30
Transmembranei57 – 78HelicalSequence analysisAdd BLAST22
Transmembranei90 – 114HelicalSequence analysisAdd BLAST25
Transmembranei124 – 149HelicalSequence analysisAdd BLAST26
Transmembranei160 – 187HelicalSequence analysisAdd BLAST28
Transmembranei192 – 220HelicalSequence analysisAdd BLAST29
Transmembranei315 – 339HelicalSequence analysisAdd BLAST25

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi474H → Q: No loss of activity. 1 Publication1
Mutagenesisi487H → Q: No loss of activity. 1 Publication1
Mutagenesisi558E → D or Q: Loss of activity. 1 Publication1
Mutagenesisi751H → Q: No loss of activity. 1 Publication1
Mutagenesisi766D → N: Loss of activity. 1 Publication1
Mutagenesisi860H → Q: No loss of activity. 1 Publication1
Mutagenesisi865H → K or Q: Loss of activity. 1 Publication1
Mutagenesisi868H → Y: No loss of activity. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL1075267

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001144201 – 8873-hydroxy-3-methylglutaryl-coenzyme A reductaseAdd BLAST887

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki89Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki248Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Glycosylationi281N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi517N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi869N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei871Phosphoserine; by AMPKBy similarity1

Post-translational modificationi

Undergoes sterol-mediated ubiquitination and ER-associated degradation (ERAD). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1. This INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78 or RNF145, 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
N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.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 databases

BindingDBiP09610

Structurei

3D structure databases

ProteinModelPortaliP09610
SMRiP09610
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini61 – 218SSDPROSITE-ProRule annotationAdd BLAST158

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni340 – 449LinkerAdd BLAST110
Regioni450 – 887CatalyticAdd BLAST438

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi75 – 78INSIG-binding motifBy similarity4

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi243 – 246Poly-Glu4

Sequence similaritiesi

Belongs to the HMG-CoA reductase family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

HOVERGENiHBG000453
OrthoDBiEOG091G0I1B

Family and domain databases

CDDicd00643 HMG-CoA_reductase_classI, 1 hit
Gene3Di1.10.3270.101 hit
3.30.70.4201 hit
3.90.770.102 hits
InterProiView protein in InterPro
IPR002202 HMG_CoA_Rdtase
IPR023074 HMG_CoA_Rdtase_cat_sf
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_sf
IPR009029 HMG_CoA_Rdtase_sub-bd_dom_sf
IPR000731 SSD
PANTHERiPTHR10572 PTHR10572, 1 hit
PfamiView protein in Pfam
PF00368 HMG-CoA_red, 1 hit
PF12349 Sterol-sensing, 1 hit
PRINTSiPR00071 HMGCOARDTASE
SUPFAMiSSF55035 SSF55035, 1 hit
SSF56542 SSF56542, 2 hits
TIGRFAMsiTIGR00920 2A060605, 1 hit
TIGR00533 HMG_CoA_R_NADP, 1 hit
PROSITEiView protein in PROSITE
PS00066 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

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

Similar proteinsi

Entry informationi

Entry nameiHMDH_MESAU
AccessioniPrimary (citable) accession number: P09610
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 1, 1989
Last sequence update: July 1, 1989
Last modified: April 25, 2018
This is version 130 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome