HMGCR

Protein identityUniProt · HPA

UniProt accession

P04035

Gene

HMGCR

Ensembl

ENSG00000113161

Chromosome

5

Canonical length

888 aa

Protein class

Enzymes, FDA approved drug targets, Metabolic proteins, Plasma proteins, Predicted intracellular proteins, Predicted membrane proteins, Transporters

Quaternary structure

Homotetramer

OverviewNCBI Gene

HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and is regulated via a negative feedback mechanism mediated by sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

Canonical amino-acid sequenceUniProt

888 residues, UniProt reviewed canonical sequence.

>P04035|HMGCR
     1  MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC PKFEEDVLSS
    61  DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI FSSFVFSTVV IHFLDKELTG
   121  LNEALPFFLL LIDLSRASTL AKFALSSNSQ DEVRENIARG MAILGPTFTL DALVECLVIG
   181  VGTMSGVRQL EIMCCFGCMS VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR
   241  VLEEEENKPN PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTADTSKVS LGLDENVSKR
   301  IEPSVSLWQF YLSKMISMDI EQVITLSLAL LLAVKYIFFE QTETESTLSL KNPITSPVVT
   361  QKKVPDNCCR REPMLVRNNQ KCDSVEEETG INRERKVEVI KPLVAETDTP NRATFVVGNS
   421  SLLDTSSVLV TQEPEIELPR EPRPNEECLQ ILGNAEKGAK FLSDAEIIQL VNAKHIPAYK
   481  LETLMETHER GVSIRRQLLS KKLSEPSSLQ YLPYRDYNYS LVMGACCENV IGYMPIPVGV
   541  AGPLCLDEKE FQVPMATTEG CLVASTNRGC RAIGLGGGAS SRVLADGMTR GPVVRLPRAC
   601  DSAEVKAWLE TSEGFAVIKE AFDSTSRFAR LQKLHTSIAG RNLYIRFQSR SGDAMGMNMI
   661  SKGTEKALSK LHEYFPEMQI LAVSGNYCTD KKPAAINWIE GRGKSVVCEA VIPAKVVREV
   721  LKTTTEAMIE VNINKNLVGS AMAGSIGGYN AHAANIVTAI YIACGQDAAQ NVGSSNCITL
   781  MEASGPTNED LYISCTMPSI EIGTVGGGTN LLPQQACLQM LGVQGACKDN PGENARQLAR
   841  IVCGTVMAGE LSLMAALAAG HLVKSHMIHN RSKINLQDLQ GACTKKTA

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against HMGCR can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Other membrane

Secreted

No

Transmembrane segments

8

Mean surface accessibility (rSASA)

0.35

Highest tissue expression

99 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about HMGCR.

Disease | AllUniProt

Conditions HMGCR is implicated in, by any mechanism.

• Muscular dystrophy, limb-girdle, autosomal recessive 28 (LGMDR28) MIM:620375

Disease | GeneticClinVar

7 pathogenic / likely-pathogenic of 99 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Muscular dystrophy, limb-girdle, autosomal recessive 28
• Limb-girdle muscular dystrophy

Disease | AutoantibodyPubMed

Conditions in which antibodies against HMGCR are reported. Each links to that disease's full target list.

• Myositis 93
• Muscle Weakness 10
• Dermatomyositis 7
• Lung Neoplasms 4

Showing 4 of 5 — disease pages carrying at least 10 antigens.

ReferencesPubMed · IEDB

Publications for HMGCR from three distinct lines of evidence, kept separate because they answer different questions: whether antibodies are directed at the protein, whether a B-cell epitope has been mapped on it, and whether a T-cell epitope has. Each is labelled with its source.

Sources: PubMed — antigen-level antibody evidence from a custom retrieval. Records matching a controlled set of autoantibody terms (the MeSH descriptors Autoantibodies and Autoantigens, with title and abstract term variants) were obtained through NCBI E-utilities, and their titles and abstracts parsed for constructions that direct an antibody at a named protein rather than for co-occurrence. Captured names were resolved against UniProt nomenclature and each antigen adjudicated individually against the source text. Bibliographic records from PubMed and MeSH, U.S. National Library of Medicine; citation metrics from NIH iCite (Hutchins et al., PLoS Biology 2016). Titles link to PubMed; abstracts are not reproduced here. The NLM does not endorse this analysis.

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.26

gnomAD pLI

1

gnomAD missense Z

3.76

DepMap mean gene effect

-1.05

DepMap dependency class

common

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 4% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• cholesterol biosynthetic process
• coenzyme A metabolic process
• isoprenoid biosynthetic process
• long-term synaptic potentiation
• negative regulation of amyloid-beta clearance
• negative regulation of protein catabolic process
• negative regulation of protein secretion
• regulation of ERK1 and ERK2 cascade
• sterol biosynthetic process
• visual learning

Molecular functions

• coenzyme A binding
• GTPase regulator activity
• NADPH binding
• hydroxymethylglutaryl-CoA reductase (NADPH) activity

Cellular components

• endoplasmic reticulum
• endoplasmic reticulum membrane
• peroxisomal membrane

Protein domainsUniProt · Pfam · InterPro

• Sterol-sensing domain
• HMGCR/SNAP/NPC1-like, sterol-sensing domain
• Sterol-sensing domain of SREBP cleavage-activation
• Hydroxymethylglutaryl-CoA reductase, class I/II
• Hydroxymethylglutaryl-CoA reductase, eukaryotic/archaeal type
• Hydroxymethylglutaryl-CoA reductase, metazoan
• Hydroxymethylglutaryl-CoA reductase, class I/II, NAD/NADP-binding domain superfamily
• Hydroxymethylglutaryl-CoA reductase, class I/II, substrate-binding domain superfamily
• Hydroxymethylglutaryl-CoA reductase, class I/II, catalytic domain superfamily
• Hydroxymethylglutaryl-CoA reductase, class I/II, conserved site
• Hydroxymethylglutaryl-CoA reductase, N-terminal
• Hydroxymethylglutaryl-coenzyme A reductase

KeywordsUniProt

• Cholesterol biosynthesis
• Cholesterol metabolism
• Endoplasmic reticulum
• Glycoprotein
• Isopeptide bond
• Limb-girdle muscular dystrophy
• Lipid biosynthesis
• Lipid metabolism
• Membrane
• NADP
• Oxidoreductase
• Peroxisome
• Phosphoprotein
• Steroid biosynthesis
• Steroid metabolism
• Sterol biosynthesis
• Sterol metabolism
• Transmembrane
• Transmembrane helix
• Ubl conjugation

InteractionsUniProt · HPA

Protein binding partners of HMGCR in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• UBIAD1
• INSIG1