P00347 · HMDH_CRIGR
- Protein3-hydroxy-3-methylglutaryl-coenzyme A reductase
- GeneHMGCR
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids887 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis.
Catalytic activity
- (R)-mevalonate + CoA + 2 NADP+ = (3S)-hydroxy-3-methylglutaryl-CoA + 2 H+ + 2 NADPHThis reaction proceeds in the backward direction.
Activity regulation
Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate (By similarity).
Phosphorylation at Ser-871 down-regulates the catalytic activity (PubMed:8415689).
Phosphorylation at Ser-871 down-regulates the catalytic activity (PubMed:8415689).
Pathway
Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
Features
Showing features for active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Active site | 558 | Charge relay system | ||||
Sequence: E | ||||||
Active site | 690 | Charge relay system | ||||
Sequence: K | ||||||
Active site | 766 | Charge relay system | ||||
Sequence: D | ||||||
Active site | 865 | Proton donor | ||||
Sequence: H |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | endoplasmic reticulum | |
Cellular Component | endoplasmic reticulum membrane | |
Cellular Component | peroxisomal membrane | |
Molecular Function | coenzyme A binding | |
Molecular Function | GTPase regulator activity | |
Molecular Function | hydroxymethylglutaryl-CoA reductase (NADPH) activity | |
Molecular Function | NADPH binding | |
Biological Process | cholesterol biosynthetic process | |
Biological Process | coenzyme A metabolic process | |
Biological Process | isoprenoid biosynthetic process | |
Biological Process | long-term synaptic potentiation | |
Biological Process | negative regulation of amyloid-beta clearance | |
Biological Process | negative regulation of protein catabolic process | |
Biological Process | negative regulation of protein secretion | |
Biological Process | regulation of ERK1 and ERK2 cascade | |
Biological Process | visual learning |
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended name3-hydroxy-3-methylglutaryl-coenzyme A reductase
- EC number
- Short namesHMG-CoA reductase
Gene names
Organism names
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Cricetidae > Cricetinae > Cricetulus
Accessions
- Primary accessionP00347
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Endoplasmic reticulum membrane ; Multi-pass membrane protein
Peroxisome membrane ; Multi-pass membrane protein
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-9 | Cytoplasmic | ||||
Sequence: MLSRLFRMH | ||||||
Transmembrane | 10-39 | Helical | ||||
Sequence: GLFVASHPWEVIVGTVTLTICMMSMNMFTG | ||||||
Topological domain | 40-56 | Lumenal | ||||
Sequence: NNKICGWNYECPKFEED | ||||||
Transmembrane | 57-78 | Helical | ||||
Sequence: VLSSDIIILTITRCIAILYIYF | ||||||
Topological domain | 79-89 | Cytoplasmic | ||||
Sequence: QFQNLRQLGSK | ||||||
Transmembrane | 90-114 | Helical | ||||
Sequence: YILGIAGLFTIFSSFVFSTVVIHFL | ||||||
Topological domain | 115-123 | Lumenal | ||||
Sequence: DKELTGLNE | ||||||
Transmembrane | 124-149 | Helical | ||||
Sequence: ALPFFLLLIDLSRASALAKFALSSNS | ||||||
Topological domain | 150-159 | Cytoplasmic | ||||
Sequence: QDEVRENIAR | ||||||
Transmembrane | 160-187 | Helical | ||||
Sequence: GMAILGPTFTLDALVECLVIGVGTMSGV | ||||||
Topological domain | 188-191 | Lumenal | ||||
Sequence: RQLE | ||||||
Transmembrane | 192-220 | Helical | ||||
Sequence: IMCCFGCMSVLANYFVFMTFFPACVSLVL | ||||||
Topological domain | 221-248 | Cytoplasmic | ||||
Sequence: ELSRESREGRPIWQLSHFARVLEEEENK | ||||||
Transmembrane | 249-275 | Helical | ||||
Sequence: PNPVTQRVKMIMSLGLVLVHAHSRWIA | ||||||
Topological domain | 276-314 | Lumenal | ||||
Sequence: DPSPQNSTTEHSKVSLGLDEDVSKRIEPSVSLWQFYLSK | ||||||
Transmembrane | 315-339 | Helical | ||||
Sequence: MISMDIEQVVTLSLAFLLAVKYIFF | ||||||
Topological domain | 340-887 | Cytoplasmic | ||||
Sequence: EQAETESTLSLKNPITSPVVTPKKAPDNCCRREPLLVRRSEKLSSVEEEPGVSQDRKVEVIKPLVVETESASRATFVLGASGTSPPVAARTQELEIELPSEPRPNEECLQILESAEKGAKFLSDAEIIQLVNAKHIPAYKLETLMETHERGVSIRRQLLSTKLPEPSSLQYLPYRDYNYSLVMGACCENVIGYMPIPVGVAGPLCLDGKEYQVPMATTEGCLVASTNRGCRAIGLGGGASSRVLADGMTRGPVVRLPRACDSAEVKAWLETPEGFAVIKDAFDSTSRFARLQKLHVTMAGRNLYIRFQSKTGDAMGMNMISKGTEKALLKLQEFFPEMQILAVSGNYCTDKKPAAINWIEGRGKTVVCEAVIPAKVVREVLKTTTEAMIDVNINKNLVGSAMAGSIGGYNAHAANIVTAIYIACGQDAAQNVGSSNCITLMEASGPTNEDLYISCTMPSIEIGTVGGGTNLLPQQACLQMLGVQGACKDNPGENARQLARIVCGTVMAGELSLMAALAAGHLVRSHMVHNRSKINLQDLQGTCTKKSA |
Keywords
- Cellular component
Phenotypes & Variants
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 60 | Abolishes sterol-mediated interaction with INSIG1, and no ubiquitination nor degradation. | ||||
Sequence: S → N | ||||||
Mutagenesis | 75 | Very little effect on the sterol-mediated ubiquitination and degradation of HMGCR. Marked reduction in the sterol-mediated ubiquitination and degradation of HMGCR; when associated with A-77. Completely abolishes the sterol effect on ubiquitination and degradation of HMGCR; when associated with A-76; A-77 and A-78. | ||||
Sequence: Y → A | ||||||
Mutagenesis | 76 | Greatly reduced sterol-mediated ubiquitination and degradation of HMGCR. Completely abolishes the sterol effect on ubiquitination and degradation of HMGCR; when associated with A-75; A-77 and A-78. | ||||
Sequence: I → A | ||||||
Mutagenesis | 77 | Greatly reduced sterol-mediated ubiquitination and degradation of HMGCR. Marked reduction in the sterol-mediated ubiquitination and degradation of HMGCR; when associated with A-75. Completely abolishes the sterol effect on ubiquitination and degradation of HMGCR; when associated with A-75; A-76 and A-78. | ||||
Sequence: Y → A | ||||||
Mutagenesis | 78 | Very little effect on the sterol-mediated ubiquitination and degradation of HMGCR. Completely abolishes the sterol effect on ubiquitination and degradation of HMGCR; when associated with A-75; A-76 and A-77. | ||||
Sequence: F → A | ||||||
Mutagenesis | 87 | Abolishes sterol-mediated interaction with INSIG1, and no ubiquitination nor degradation. | ||||
Sequence: G → R | ||||||
Mutagenesis | 89 | Little effect on sterol plus mevalonate-stimulated ubiquitination and degradation of HMGCR in the presence of INSIG1. No sterol plus mevalonate-stimulated ubiquitination and degradation of HMGCR in the presence of INSIG1; when associated with R-248. | ||||
Sequence: K → R | ||||||
Mutagenesis | 248 | Some reduction in sterol plus mevalonate-stimulated ubiquitination and degradation of HMGCR in the presence of INSIG1. No sterol plus mevalonate-stimulated ubiquitination and degradation of HMGCR in the presence of INSIG1; when associated with R-89. | ||||
Sequence: K → R | ||||||
Mutagenesis | 333 | Abolishes sterol-mediated interaction with INSIG1, and no ubiquitination nor degradation. | ||||
Sequence: A → P | ||||||
Mutagenesis | 871 | Abolishes phosphorylation by AMPK. Blocks inhibition of sterol synthesis induced by ATP depletion. | ||||
Sequence: S → A |
Chemistry
PTM/Processing
Features
Showing features for chain, cross-link, glycosylation, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000114418 | 1-887 | 3-hydroxy-3-methylglutaryl-coenzyme A reductase | |||
Sequence: MLSRLFRMHGLFVASHPWEVIVGTVTLTICMMSMNMFTGNNKICGWNYECPKFEEDVLSSDIIILTITRCIAILYIYFQFQNLRQLGSKYILGIAGLFTIFSSFVFSTVVIHFLDKELTGLNEALPFFLLLIDLSRASALAKFALSSNSQDEVRENIARGMAILGPTFTLDALVECLVIGVGTMSGVRQLEIMCCFGCMSVLANYFVFMTFFPACVSLVLELSRESREGRPIWQLSHFARVLEEEENKPNPVTQRVKMIMSLGLVLVHAHSRWIADPSPQNSTTEHSKVSLGLDEDVSKRIEPSVSLWQFYLSKMISMDIEQVVTLSLAFLLAVKYIFFEQAETESTLSLKNPITSPVVTPKKAPDNCCRREPLLVRRSEKLSSVEEEPGVSQDRKVEVIKPLVVETESASRATFVLGASGTSPPVAARTQELEIELPSEPRPNEECLQILESAEKGAKFLSDAEIIQLVNAKHIPAYKLETLMETHERGVSIRRQLLSTKLPEPSSLQYLPYRDYNYSLVMGACCENVIGYMPIPVGVAGPLCLDGKEYQVPMATTEGCLVASTNRGCRAIGLGGGASSRVLADGMTRGPVVRLPRACDSAEVKAWLETPEGFAVIKDAFDSTSRFARLQKLHVTMAGRNLYIRFQSKTGDAMGMNMISKGTEKALLKLQEFFPEMQILAVSGNYCTDKKPAAINWIEGRGKTVVCEAVIPAKVVREVLKTTTEAMIDVNINKNLVGSAMAGSIGGYNAHAANIVTAIYIACGQDAAQNVGSSNCITLMEASGPTNEDLYISCTMPSIEIGTVGGGTNLLPQQACLQMLGVQGACKDNPGENARQLARIVCGTVMAGELSLMAALAAGHLVRSHMVHNRSKINLQDLQGTCTKKSA | ||||||
Cross-link | 89 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Cross-link | 248 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Glycosylation | 281 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Modified residue | 871 | Phosphoserine; by AMPK | ||||
Sequence: S |
Post-translational modification
N-glycosylated. Glycosylated with high mannose chains including Man6(GlcNAc)2, Man7(GlcNAc)2 and Man8(GlcNAc)2 (PubMed:6580634).
Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner (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-associated degradation (ERAD) (PubMed:14563840, PubMed:15247208, PubMed:17090658, PubMed:29374057).
Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1 or INSIG2 (PubMed:14563840, PubMed:17090658).
The INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating ubiquitination of the reductase (PubMed:14563840, PubMed:29374057).
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 (PubMed:14563840).
The INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, initiating ubiquitination of the reductase (By similarity).
Lys-248 is the main site of ubiquitination (PubMed:14563840, PubMed:15247208).
Ubiquitination is enhanced by the presence of a geranylgeranylated protein (By similarity).
Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1 or INSIG2 (PubMed:14563840, PubMed:17090658).
The INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating ubiquitination of the reductase (PubMed:14563840, PubMed:29374057).
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 (PubMed:14563840).
The INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, initiating ubiquitination of the reductase (By similarity).
Lys-248 is the main site of ubiquitination (PubMed:14563840, PubMed:15247208).
Ubiquitination is enhanced by the presence of a geranylgeranylated protein (By similarity).
Phosphorylated. Phosphorylation at Ser-871 reduces the catalytic activity.
Keywords
- PTM
Proteomic databases
PTM databases
Interaction
Subunit
Homotetramer. Homodimer. Interacts (via its SSD) with INSIG1; the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway (PubMed:17090658).
Interacts with UBIAD1 (By similarity).
Interacts with UBIAD1 (By similarity).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
XENO | P00347 | ERLIN2 O94905 | 2 | EBI-11426687, EBI-4400770 | |
XENO | P00347 | INSIG1 O15503 | 2 | EBI-11426687, EBI-6252425 |
Protein-protein interaction databases
Chemistry
Structure
Family & Domains
Features
Showing features for domain, motif.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 61-218 | SSD | ||||
Sequence: DIIILTITRCIAILYIYFQFQNLRQLGSKYILGIAGLFTIFSSFVFSTVVIHFLDKELTGLNEALPFFLLLIDLSRASALAKFALSSNSQDEVRENIARGMAILGPTFTLDALVECLVIGVGTMSGVRQLEIMCCFGCMSVLANYFVFMTFFPACVSL | ||||||
Motif | 75-78 | INSIG-binding motif | ||||
Sequence: YIYF |
Sequence similarities
Belongs to the HMG-CoA reductase family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length887
- Mass (Da)97,081
- Last updated1986-07-21 v1
- Checksum4331E53ADA250E6A
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
L00183 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00166 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00169 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00170 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00171 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00173 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00176 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00177 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00178 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00179 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00180 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00181 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
L00182 EMBL· GenBank· DDBJ | AAA36989.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
X00494 EMBL· GenBank· DDBJ | CAA25189.1 EMBL· GenBank· DDBJ | Genomic DNA |