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Q01237

- HMDH_MOUSE

UniProt

Q01237 - HMDH_MOUSE

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
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    • History
      Entry version 129 (01 Oct 2014)
      Sequence version 3 (03 Oct 2012)
      Previous versions | rss
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    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

    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

    GO - Cellular componenti

    1. endoplasmic reticulum membrane Source: UniProtKB-SubCell
    2. integral component of membrane Source: UniProtKB-KW
    3. peroxisomal membrane Source: Ensembl

    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

    PaxDbiQ01237.
    PRIDEiQ01237.

    PTM databases

    PhosphoSiteiQ01237.

    Expressioni

    Gene expression databases

    ArrayExpressiQ01237.
    CleanExiMM_HMGCR.
    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...

    Transmembrane

    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

    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.
    GeneTreeiENSGT00390000006426.
    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

    MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC    50
    PKFEEDVLSS DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI 100
    FSSFVFSTVV IHFLDKELTG LNEALPFFLL LIDLSRASAL AKFALSSNSQ 150
    DEVRENIARG MAILGPTFTL DALVECLVIG VGTMSGVRQL EIMCCFGCMS 200
    VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR VLEEEENKPN 250
    PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTAEQAKVS LGLDEDVSKR 300
    IEPSVSLWQF YLSKMISMDI EQVITLSLAF LLAVKYIFFE QAETESTLSL 350
    KNPITSPVVT SKKAQDNCCR REPLLVRRNQ KLSSVEEDPG ANQERKVEVI 400
    KPLVVEAETT SRATFVLGAS VASPPSALGT QEPGIELPIE PRPNEECLQI 450
    LENAEKGAKF LSDAEIIQLV NAKHIPAYKL ETLMETHERG VSIRRQLLST 500
    KLAEPSSLQY LPYRDYNYSL VMGACCENVI GYMPIPVGVA GPLCLDGKEY 550
    QVPMATTEGC LVASTNRGCR AISLGGGASS RVLADGMTRG PVVRLPRACD 600
    SAEVKTWLET PEGFAVIKEA FDSTSRFARL QKLHVTMAGR NLYIRFQSRT 650
    GDAMGMNMIS KGTEKALLKL QEFFPDMQIL AVSGNYCTDK KPAAINWIEG 700
    RGKTVVCEAV IPAKVVREVL KTTTEAMVDV NINKNLVGSA MAGSIGGYNA 750
    HAANIVTAIY IACGQDAAQN VGSSNCITLM EASGPTNEDL YISCTMPSIE 800
    IGTVGGGTNL LPQQACLQML GVQGACKDNP GENARQLARI VCGTVMAGEL 850
    SLMAALAAGH LVRSHMVHNR SKINLQDLQG TCTKKAA 887
    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:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    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

    ChEMBLi CHEMBL2764.
    GuidetoPHARMACOLOGYi 639.

    PTM databases

    PhosphoSitei Q01237.

    Proteomic databases

    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 ENSGT00390000006426.
    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

    ArrayExpressi Q01237.
    CleanExi MM_HMGCR.
    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

    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: October 1, 2014
    This is version 129 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