4yhj

Publication Abstract from PubMed

G protein-coupled receptor (GPCR) kinases (GRKs) bind to and phosphorylate GPCRs, initiating the process of GPCR desensitization and internalization. GRK4 is implicated in the regulation of blood pressure, and three GRK4 polymorphisms (R65L, A142V and A486V) are associated with hypertension. Here we describe the 2.6 A structure of human GRK4alpha A486V crystallized in the presence of AMPPNP. The structure of GRK4alpha is similar to other GRKs, although slight differences exist within the RH bundle subdomain, substrate binding site and kinase C-tail. The RH bundle subdomain and kinase C-terminal lobe form a strikingly acidic surface, whilst the kinase N-terminal lobe and RH terminal subdomain surfaces are much more basic. In this respect, GRK4alpha is more similar to GRK2 than GRK6. A fully ordered kinase C-tail reveals interactions linking the C-tail with important determinants of kinase activity, including the alphaB helix, alphaD helix and the P-loop. Autophosphorylation of wild-type GRK4alpha is required for full kinase activity, as indicated by a lag in phosphorylation of a peptide from the Dopamine D1 Receptor without ATP preincubation. In contrast this lag is not observed in GRK4alpha A486V. Phosphopeptide mapping by mass spectrometry indicates an increased rate of autophosphorylation of a number of residues in GRK4alpha A486V relative to wild-type GRK4alpha including S485 in the kinase C-tail.

Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4.,Allen SJ, Parthasarathy G, Darke PL, Diehl RE, Ford RE, Hall DL, Johnson SA, Reid JC, Rickert KW, Shipman JM, Soisson SM, Zuck P, Munshi SK, Lumb KJ J Biol Chem. 2015 Jul 1. pii: jbc.M115.648907. PMID:26134571^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.