ID:GRK5_HUMAN DESCRIPTION: RecName: Full=G protein-coupled receptor kinase 5; EC=2.7.11.16; AltName: Full=G protein-coupled receptor kinase GRK5; FUNCTION: Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein- coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70- interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2- mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G- protein-coupled receptor, LRP6 during Wnt signaling (in vitro). CATALYTIC ACTIVITY: ATP + [G-protein-coupled receptor] = ADP + [G- protein-coupled receptor] phosphate. ENZYME REGULATION: Inhibited by calmodulin with an IC(50) of 50 nM. Calmodulin inhibits GRK5 association with receptor and phospholipid. SUBUNIT: Interacts with ST13 (via the C-terminus 303-319 AA). Interacts with TP53/p53. Interacts with HTR4 (via C-terminus 330- 346 AA); this interaction is promoted by 5-HT (serotonin). Interacts with HDAC5 (By similarity). SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane; Peripheral membrane protein. Note=Predominantly localized at the plasma membrane; targeted to the cell surface through the interaction with phospholipids. Nucleus localization is regulated in a GPCR and Ca(2+)/calmodulin-dependent fashion. TISSUE SPECIFICITY: Highest levels in heart, placenta, lung > skeletal muscle > brain, liver, pancreas > kidney. INDUCTION: Overexpressed during heart failure. PTM: Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity. POLYMORPHISM: Variant Leu-41 variant is rare in European-Americans individuals but common in African-Americans individuals (40% of the African-American individuals studied carry at least one allele). Variant leu-41 is associated with decreased mortality in African-Americans with heart failure or cardiac ischemia. SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily. SIMILARITY: Contains 1 AGC-kinase C-terminal domain. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 RGS domain.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00069 - Protein kinase domain PF00615 - Regulator of G protein signaling domain PF07714 - Protein tyrosine and serine/threonine kinase PF08257 - Sulfakinin family
SCOP Domains: 48097 - Regulator of G-protein signaling, RGS 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on P34947
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
