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Q01237 (HMDH_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified March 19, 2014. Version 126. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
3-hydroxy-3-methylglutaryl-coenzyme A reductase

Short name=HMG-CoA reductase
EC=1.1.1.34
Gene names
Name:Hmgcr
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length887 AA.
Sequence statusComplete.
Protein existenceEvidence at transcript level

General annotation (Comments)

Function

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 activity

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

Enzyme regulation

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

Pathway

Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.

Subunit structure

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.

Subcellular location

Endoplasmic reticulum membrane; Multi-pass membrane protein By similarity.

Post-translational modification

N-glycosylated By similarity. 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.

Sequence similarities

Belongs to the HMG-CoA reductase family.

Contains 1 SSD (sterol-sensing) domain.

Ontologies

Keywords
   Biological processCholesterol biosynthesis
Cholesterol metabolism
Lipid biosynthesis
Lipid metabolism
Steroid biosynthesis
Steroid metabolism
Sterol biosynthesis
Sterol metabolism
   Cellular componentEndoplasmic reticulum
Membrane
   DomainTransmembrane
Transmembrane helix
   LigandNADP
   Molecular functionOxidoreductase
   PTMGlycoprotein
Isopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processaging

Inferred from electronic annotation. Source: Ensembl

cholesterol biosynthetic process

Inferred from direct assay PubMed 15845870PubMed 7798939PubMed 8647961. Source: MGI

coenzyme A metabolic process

Inferred from electronic annotation. Source: InterPro

embryo development

Inferred from mutant phenotype PubMed 12920113. Source: MGI

isoprenoid biosynthetic process

Inferred from electronic annotation. Source: Ensembl

myoblast differentiation

Inferred from electronic annotation. Source: Ensembl

negative regulation of MAP kinase activity

Inferred from genetic interaction PubMed 12409258. Source: MGI

negative regulation of insulin secretion involved in cellular response to glucose stimulus

Inferred from electronic annotation. Source: Ensembl

negative regulation of striated muscle cell apoptotic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of vasodilation

Inferred from electronic annotation. Source: Ensembl

negative regulation of wound healing

Inferred from electronic annotation. Source: Ensembl

positive regulation of ERK1 and ERK2 cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of cardiac muscle cell apoptotic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of skeletal muscle tissue development

Inferred from electronic annotation. Source: Ensembl

positive regulation of smooth muscle cell proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of stress-activated MAPK cascade

Inferred from electronic annotation. Source: Ensembl

protein tetramerization

Inferred from electronic annotation. Source: Ensembl

response to ethanol

Inferred from electronic annotation. Source: Ensembl

response to nutrient

Inferred from electronic annotation. Source: Ensembl

ubiquinone metabolic process

Inferred from electronic annotation. Source: Ensembl

visual learning

Inferred from genetic interaction PubMed 12409258. Source: MGI

   Cellular_componentendoplasmic reticulum membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

peroxisomal membrane

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionNADPH binding

Inferred from electronic annotation. Source: Ensembl

hydroxymethylglutaryl-CoA reductase (NADPH) activity

Inferred from direct assay PubMed 11792727PubMed 12114517PubMed 12920113PubMed 1352323PubMed 15845870PubMed 16100574PubMed 7798939PubMed 8647961PubMed 9186920. Source: MGI

hydroxymethylglutaryl-CoA reductase activity

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 8878873-hydroxy-3-methylglutaryl-coenzyme A reductase
PRO_0000114421

Regions

Transmembrane10 – 3930Helical; Potential
Transmembrane57 – 7822Helical; Potential
Transmembrane90 – 11425Helical; Potential
Transmembrane124 – 14926Helical; Potential
Transmembrane160 – 18728Helical; Potential
Transmembrane192 – 22029Helical; Potential
Transmembrane315 – 33925Helical; Potential
Domain61 – 218158SSD
Region340 – 449110Linker
Region450 – 887438Catalytic
Motif75 – 784INSIG-binding motif By similarity
Compositional bias243 – 2464Poly-Glu

Sites

Active site5581Charge relay system By similarity
Active site6901Charge relay system By similarity
Active site7661Charge relay system By similarity
Active site8651Proton donor By similarity

Amino acid modifications

Modified residue8711Phosphoserine; by AMPK By similarity
Glycosylation2811N-linked (GlcNAc...) Potential
Glycosylation5171N-linked (GlcNAc...) Potential
Glycosylation8691N-linked (GlcNAc...) Potential
Cross-link89Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Cross-link248Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Experimental info

Sequence conflict2581M → I in AAH85083. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Q01237 [UniParc].

Last modified October 3, 2012. Version 3.
Checksum: DD77B40CE66ABF92

FASTA88797,040
        10         20         30         40         50         60 
MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC PKFEEDVLSS 

        70         80         90        100        110        120 
DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI FSSFVFSTVV IHFLDKELTG 

       130        140        150        160        170        180 
LNEALPFFLL LIDLSRASAL AKFALSSNSQ DEVRENIARG MAILGPTFTL DALVECLVIG 

       190        200        210        220        230        240 
VGTMSGVRQL EIMCCFGCMS VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR 

       250        260        270        280        290        300 
VLEEEENKPN PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTAEQAKVS LGLDEDVSKR 

       310        320        330        340        350        360 
IEPSVSLWQF YLSKMISMDI EQVITLSLAF LLAVKYIFFE QAETESTLSL KNPITSPVVT 

       370        380        390        400        410        420 
SKKAQDNCCR REPLLVRRNQ KLSSVEEDPG ANQERKVEVI KPLVVEAETT SRATFVLGAS 

       430        440        450        460        470        480 
VASPPSALGT QEPGIELPIE PRPNEECLQI LENAEKGAKF LSDAEIIQLV NAKHIPAYKL 

       490        500        510        520        530        540 
ETLMETHERG VSIRRQLLST KLAEPSSLQY LPYRDYNYSL VMGACCENVI GYMPIPVGVA 

       550        560        570        580        590        600 
GPLCLDGKEY QVPMATTEGC LVASTNRGCR AISLGGGASS RVLADGMTRG PVVRLPRACD 

       610        620        630        640        650        660 
SAEVKTWLET PEGFAVIKEA FDSTSRFARL QKLHVTMAGR NLYIRFQSRT GDAMGMNMIS 

       670        680        690        700        710        720 
KGTEKALLKL QEFFPDMQIL AVSGNYCTDK KPAAINWIEG RGKTVVCEAV IPAKVVREVL 

       730        740        750        760        770        780 
KTTTEAMVDV NINKNLVGSA MAGSIGGYNA HAANIVTAIY IACGQDAAQN VGSSNCITLM 

       790        800        810        820        830        840 
EASGPTNEDL YISCTMPSIE IGTVGGGTNL LPQQACLQML GVQGACKDNP GENARQLARI 

       850        860        870        880 
VCGTVMAGEL SLMAALAAGH LVRSHMVHNR SKINLQDLQG TCTKKAA 

« Hide

References

« Hide 'large scale' references
[1]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6J.
[2]Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: FVB/N.
Tissue: Mammary tumor.
[4]"Glucocorticoid-regulated gene expression in the immune system. Analysis of glucocorticoid-regulated transcripts from the mouse macrophage-like cell line P388D1."
Helmberg A., Faessler R., Geley S., Joehrer K., Kroemer G., Boeck G., Kofler R.
J. Immunol. 145:4332-4337(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 664-887.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AC154851 Genomic DNA. No translation available.
CH466567 Genomic DNA. Translation: EDL00884.1.
BC085083 mRNA. Translation: AAH85083.1.
M62766 mRNA. Translation: AAA37819.1.
PIRA43533.
RefSeqNP_032281.2. NM_008255.2.
XP_006517594.1. XM_006517531.1.
XP_006517595.1. XM_006517532.1.
UniGeneMm.316652.

3D structure databases

ProteinModelPortalQ01237.
SMRQ01237. Positions 440-862.
ModBaseSearch...
MobiDBSearch...

Chemistry

ChEMBLCHEMBL2764.
GuidetoPHARMACOLOGY639.

PTM databases

PhosphoSiteQ01237.

Proteomic databases

PaxDbQ01237.
PRIDEQ01237.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000022176; ENSMUSP00000022176; ENSMUSG00000021670.
GeneID15357.
KEGGmmu:15357.
UCSCuc007rnm.3. mouse.

Organism-specific databases

CTD3156.
MGIMGI:96159. Hmgcr.

Phylogenomic databases

eggNOGCOG1257.
GeneTreeENSGT00390000006426.
HOGENOMHOG000183489.
HOVERGENHBG000453.
InParanoidQ01237.
KOK00021.
OMAPNEECLQ.
OrthoDBEOG7GXP9T.
TreeFamTF105362.

Enzyme and pathway databases

SABIO-RKQ01237.
UniPathwayUPA00058; UER00103.

Gene expression databases

ArrayExpressQ01237.
CleanExMM_HMGCR.
GenevestigatorQ01237.

Family and domain databases

Gene3D1.10.3270.10. 1 hit.
3.30.70.420. 1 hit.
3.90.770.10. 2 hits.
InterProIPR002202. 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.
IPR009029. HMG_CoA_Rdtase_sub-bd.
IPR000731. SSD.
[Graphical view]
PANTHERPTHR10572. PTHR10572. 1 hit.
PfamPF00368. HMG-CoA_red. 1 hit.
[Graphical view]
PRINTSPR00071. HMGCOARDTASE.
SUPFAMSSF55035. SSF55035. 1 hit.
SSF56542. SSF56542. 2 hits.
TIGRFAMsTIGR00920. 2A060605. 1 hit.
TIGR00533. HMG_CoA_R_NADP. 1 hit.
PROSITEPS00066. 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]
ProtoNetSearch...

Other

ChiTaRSHmgcr. mouse.
NextBio287972.
PROQ01237.
SOURCESearch...

Entry information

Entry nameHMDH_MOUSE
AccessionPrimary (citable) accession number: Q01237
Secondary accession number(s): G3X8U5, Q5U4I2
Entry history
Integrated into UniProtKB/Swiss-Prot: July 1, 1993
Last sequence update: October 3, 2012
Last modified: March 19, 2014
This is version 126 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PATHWAY comments

Index of metabolic and biosynthesis pathways

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot