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Q01237

- HMDH_MOUSE

UniProt

Q01237 - HMDH_MOUSE

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Protein

3-hydroxy-3-methylglutaryl-coenzyme A reductase

Gene

Hmgcr

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at transcript 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

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

  1. hydroxymethylglutaryl-CoA reductase (NADPH) activity Source: MGI
  2. hydroxymethylglutaryl-CoA reductase activity Source: Ensembl
  3. NADPH binding Source: Ensembl

GO - Biological processi

  1. aging Source: Ensembl
  2. cholesterol biosynthetic process Source: MGI
  3. coenzyme A metabolic process Source: InterPro
  4. isoprenoid biosynthetic process Source: Ensembl
  5. myoblast differentiation Source: Ensembl
  6. negative regulation of insulin secretion involved in cellular response to glucose stimulus Source: Ensembl
  7. negative regulation of MAP kinase activity Source: MGI
  8. negative regulation of striated muscle cell apoptotic process Source: Ensembl
  9. negative regulation of vasodilation Source: Ensembl
  10. negative regulation of wound healing Source: Ensembl
  11. positive regulation of cardiac muscle cell apoptotic process Source: Ensembl
  12. positive regulation of ERK1 and ERK2 cascade Source: Ensembl
  13. positive regulation of skeletal muscle tissue development Source: Ensembl
  14. positive regulation of smooth muscle cell proliferation Source: Ensembl
  15. positive regulation of stress-activated MAPK cascade Source: Ensembl
  16. protein tetramerization Source: Ensembl
  17. response to ethanol Source: Ensembl
  18. response to nutrient Source: Ensembl
  19. ubiquinone metabolic process Source: Ensembl
  20. visual learning Source: MGI
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

ReactomeiREACT_198602. PPARA activates gene expression.
REACT_198969. Activation of gene expression by SREBF (SREBP).
REACT_208531. Cholesterol biosynthesis.
SABIO-RKQ01237.
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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 13

Organism-specific databases

MGIiMGI:96159. Hmgcr.

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

  1. endoplasmic reticulum membrane Source: InterPro
  2. integral component of membrane Source: UniProtKB-KW
  3. peroxisomal membrane Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 8878873-hydroxy-3-methylglutaryl-coenzyme A reductasePRO_0000114421Add
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

Proteomic databases

MaxQBiQ01237.
PaxDbiQ01237.
PRIDEiQ01237.

PTM databases

PhosphoSiteiQ01237.

Expressioni

Gene expression databases

CleanExiMM_HMGCR.
ExpressionAtlasiQ01237. baseline and differential.
GenevestigatoriQ01237.

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

Structurei

3D structure databases

ProteinModelPortaliQ01237.
SMRiQ01237. Positions 440-862.
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

eggNOGiCOG1257.
GeneTreeiENSGT00760000119321.
HOGENOMiHOG000183489.
HOVERGENiHBG000453.
InParanoidiQ01237.
KOiK00021.
OMAiPNEECLQ.
OrthoDBiEOG7GXP9T.
TreeFamiTF105362.

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.
[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.

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

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti258 – 2581M → I in AAH85083. (PubMed:15489334)Curated

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.
XP_006517595.1. XM_006517532.1.
UniGeneiMm.316652.

Genome annotation databases

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

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 .
CCDSi CCDS26706.1.
PIRi A43533.
RefSeqi NP_032281.2. NM_008255.2.
XP_006517594.1. XM_006517531.1.
XP_006517595.1. XM_006517532.1.
UniGenei Mm.316652.

3D structure databases

ProteinModelPortali Q01237.
SMRi Q01237. Positions 440-862.
ModBasei Search...
MobiDBi Search...

Chemistry

BindingDBi Q01237.
ChEMBLi CHEMBL2764.
GuidetoPHARMACOLOGYi 639.

PTM databases

PhosphoSitei Q01237.

Proteomic databases

MaxQBi Q01237.
PaxDbi Q01237.
PRIDEi Q01237.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000022176 ; ENSMUSP00000022176 ; ENSMUSG00000021670 .
GeneIDi 15357.
KEGGi mmu:15357.
UCSCi uc007rnm.3. mouse.

Organism-specific databases

CTDi 3156.
MGIi MGI:96159. Hmgcr.

Phylogenomic databases

eggNOGi COG1257.
GeneTreei ENSGT00760000119321.
HOGENOMi HOG000183489.
HOVERGENi HBG000453.
InParanoidi Q01237.
KOi K00021.
OMAi PNEECLQ.
OrthoDBi EOG7GXP9T.
TreeFami TF105362.

Enzyme and pathway databases

UniPathwayi UPA00058 ; UER00103 .
Reactomei REACT_198602. PPARA activates gene expression.
REACT_198969. Activation of gene expression by SREBF (SREBP).
REACT_208531. Cholesterol biosynthesis.
SABIO-RK Q01237.

Miscellaneous databases

ChiTaRSi Hmgcr. mouse.
NextBioi 287972.
PROi Q01237.
SOURCEi Search...

Gene expression databases

CleanExi MM_HMGCR.
ExpressionAtlasi Q01237. baseline and differential.
Genevestigatori Q01237.

Family and domain databases

Gene3Di 1.10.3270.10. 1 hit.
3.30.70.420. 1 hit.
3.90.770.10. 2 hits.
InterProi IPR002202. 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 ]
PANTHERi PTHR10572. PTHR10572. 1 hit.
Pfami PF00368. HMG-CoA_red. 1 hit.
[Graphical view ]
PRINTSi PR00071. HMGCOARDTASE.
SUPFAMi SSF55035. SSF55035. 1 hit.
SSF56542. SSF56542. 2 hits.
TIGRFAMsi TIGR00920. 2A060605. 1 hit.
TIGR00533. HMG_CoA_R_NADP. 1 hit.
PROSITEi 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.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. 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.

Entry informationi

Entry nameiHMDH_MOUSE
AccessioniPrimary (citable) accession number: Q01237
Secondary accession number(s): G3X8U5, Q5U4I2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 1, 1993
Last sequence update: October 3, 2012
Last modified: November 26, 2014
This is version 131 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

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

External Data

Dasty 3