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Protein

3-hydroxy-3-methylglutaryl-coenzyme A reductase

Gene

Hmgcr

Organism
Mus musculus (Mouse)
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

Activity 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. Hydroxymethylglutaryl-CoA synthase, cytoplasmic (Hmgcs1), Hydroxymethylglutaryl-CoA synthase, mitochondrial (Hmgcs2), 3-hydroxy-3-methylglutaryl coenzyme A synthase (Hmgcs1), 3-hydroxy-3-methylglutaryl coenzyme A synthase (Hmgcs2), 3-hydroxy-3-methylglutaryl coenzyme A synthase (Hmgcs1), 3-hydroxy-3-methylglutaryl coenzyme A synthase (Hmgcs1), 3-hydroxy-3-methylglutaryl coenzyme A synthase (Hmgcs1), 3-hydroxy-3-methylglutaryl coenzyme A synthase (Hmgcs1)
  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), 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

ReactomeiR-MMU-191273 Cholesterol biosynthesis
SABIO-RKiQ01237
UniPathwayi
UPA00058;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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 13

Organism-specific databases

MGIiMGI:96159 Hmgcr

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

Chemistry databases

ChEMBLiCHEMBL2764
GuidetoPHARMACOLOGYi639

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001144211 – 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 residuei871PhosphoserineCombined sources1

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

Proteomic databases

EPDiQ01237
MaxQBiQ01237
PaxDbiQ01237
PeptideAtlasiQ01237
PRIDEiQ01237

PTM databases

iPTMnetiQ01237
PhosphoSitePlusiQ01237

Expressioni

Gene expression databases

BgeeiENSMUSG00000021670 Expressed in 284 organ(s), highest expression level in liver
CleanExiMM_HMGCR
ExpressionAtlasiQ01237 baseline and differential
GenevisibleiQ01237 MM

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

GO - Molecular functioni

Protein-protein interaction databases

BioGridi200338, 2 interactors
STRINGi10090.ENSMUSP00000022176

Chemistry databases

BindingDBiQ01237

Structurei

3D structure databases

ProteinModelPortaliQ01237
SMRiQ01237
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

eggNOGiKOG2480 Eukaryota
COG1257 LUCA
GeneTreeiENSGT00910000144151
HOGENOMiHOG000183489
HOVERGENiHBG000453
InParanoidiQ01237
KOiK00021
OMAiCASHPWE
OrthoDBiEOG091G0I1B
TreeFamiTF105362

Family and domain databases

CDDicd00643 HMG-CoA_reductase_classI, 1 hit
Gene3Di1.10.3270.10, 1 hit
3.30.70.420, 1 hit
3.90.770.10, 1 hit
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, 1 hit
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

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 7 potential isoforms that are computationally mapped.Show allAlign All

Q01237-1 [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 NSTAEQAKVS LGLDEDVSKR
310 320 330 340 350
IEPSVSLWQF YLSKMISMDI EQVITLSLAF LLAVKYIFFE QAETESTLSL
360 370 380 390 400
KNPITSPVVT SKKAQDNCCR REPLLVRRNQ KLSSVEEDPG ANQERKVEVI
410 420 430 440 450
KPLVVEAETT SRATFVLGAS VASPPSALGT QEPGIELPIE PRPNEECLQI
460 470 480 490 500
LENAEKGAKF LSDAEIIQLV NAKHIPAYKL ETLMETHERG VSIRRQLLST
510 520 530 540 550
KLAEPSSLQY LPYRDYNYSL VMGACCENVI GYMPIPVGVA GPLCLDGKEY
560 570 580 590 600
QVPMATTEGC LVASTNRGCR AISLGGGASS RVLADGMTRG PVVRLPRACD
610 620 630 640 650
SAEVKTWLET PEGFAVIKEA FDSTSRFARL QKLHVTMAGR NLYIRFQSRT
660 670 680 690 700
GDAMGMNMIS KGTEKALLKL QEFFPDMQIL AVSGNYCTDK KPAAINWIEG
710 720 730 740 750
RGKTVVCEAV IPAKVVREVL KTTTEAMVDV 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):97,040
Last modified:October 3, 2012 - v3
Checksum:iDD77B40CE66ABF92
GO

Computationally mapped potential isoform sequencesi

There are 7 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
F2Z470F2Z470_MOUSE
3-hydroxy-3-methylglutaryl coenzyme...
Hmgcr
819Annotation score:
E9PY17E9PY17_MOUSE
3-hydroxy-3-methylglutaryl-coenzyme...
Hmgcr
210Annotation score:
E9Q5H3E9Q5H3_MOUSE
3-hydroxy-3-methylglutaryl-coenzyme...
Hmgcr
91Annotation score:
E9PVG9E9PVG9_MOUSE
3-hydroxy-3-methylglutaryl-coenzyme...
Hmgcr
100Annotation score:
F6X166F6X166_MOUSE
3-hydroxy-3-methylglutaryl-coenzyme...
Hmgcr
218Annotation score:
F7CA39F7CA39_MOUSE
3-hydroxy-3-methylglutaryl-coenzyme...
Hmgcr
165Annotation score:
E9Q149E9Q149_MOUSE
3-hydroxy-3-methylglutaryl-coenzyme...
Hmgcr
52Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti258M → I in AAH85083 (PubMed:15489334).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AC154851 Genomic DNA No translation available.
CH466567 Genomic DNA Translation: EDL00884.1
BC085083 mRNA Translation: AAH85083.1
M62766 mRNA Translation: AAA37819.1
CCDSiCCDS26706.1
PIRiA43533
RefSeqiNP_032281.2, NM_008255.2
XP_006517594.1, XM_006517531.1
UniGeneiMm.316652

Genome annotation databases

EnsembliENSMUST00000022176; ENSMUSP00000022176; ENSMUSG00000021670
GeneIDi15357
KEGGimmu:15357
UCSCiuc007rnm.3 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AC154851 Genomic DNA No translation available.
CH466567 Genomic DNA Translation: EDL00884.1
BC085083 mRNA Translation: AAH85083.1
M62766 mRNA Translation: AAA37819.1
CCDSiCCDS26706.1
PIRiA43533
RefSeqiNP_032281.2, NM_008255.2
XP_006517594.1, XM_006517531.1
UniGeneiMm.316652

3D structure databases

ProteinModelPortaliQ01237
SMRiQ01237
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi200338, 2 interactors
STRINGi10090.ENSMUSP00000022176

Chemistry databases

BindingDBiQ01237
ChEMBLiCHEMBL2764
GuidetoPHARMACOLOGYi639

PTM databases

iPTMnetiQ01237
PhosphoSitePlusiQ01237

Proteomic databases

EPDiQ01237
MaxQBiQ01237
PaxDbiQ01237
PeptideAtlasiQ01237
PRIDEiQ01237

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000022176; ENSMUSP00000022176; ENSMUSG00000021670
GeneIDi15357
KEGGimmu:15357
UCSCiuc007rnm.3 mouse

Organism-specific databases

CTDi3156
MGIiMGI:96159 Hmgcr

Phylogenomic databases

eggNOGiKOG2480 Eukaryota
COG1257 LUCA
GeneTreeiENSGT00910000144151
HOGENOMiHOG000183489
HOVERGENiHBG000453
InParanoidiQ01237
KOiK00021
OMAiCASHPWE
OrthoDBiEOG091G0I1B
TreeFamiTF105362

Enzyme and pathway databases

UniPathwayi
UPA00058;UER00103

ReactomeiR-MMU-191273 Cholesterol biosynthesis
SABIO-RKiQ01237

Miscellaneous databases

ChiTaRSiHmgcr mouse
PROiPR:Q01237
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000021670 Expressed in 284 organ(s), highest expression level in liver
CleanExiMM_HMGCR
ExpressionAtlasiQ01237 baseline and differential
GenevisibleiQ01237 MM

Family and domain databases

CDDicd00643 HMG-CoA_reductase_classI, 1 hit
Gene3Di1.10.3270.10, 1 hit
3.30.70.420, 1 hit
3.90.770.10, 1 hit
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, 1 hit
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
ProtoNetiSearch...

Entry informationi

Entry nameiHMDH_MOUSE
AccessioniPrimary (citable) accession number: Q01237
Secondary accession number(s): G3X8U5, Q5U4I2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 1, 1993
Last sequence update: October 3, 2012
Last modified: November 7, 2018
This is version 163 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. PATHWAY comments
    Index of metabolic and biosynthesis pathways
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Main funding by: National Institutes of Health

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