Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4

Allen, Samantha J.; Parthasarathy, Gopal; Darke, Paul L.; Diehl, Ronald E.; Ford, Rachael E.; Hall, Dawn L.; Johnson, Scott A.; Reid, John C.; Rickert, Keith W.; Shipman, Jennifer M.; Soisson, Stephen M.; Zuck, Paul; Munshi, Sanjeev K.; Lumb, Kevin J.

doi:10.1074/jbc.m115.648907

Title: Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4

Journal Article · Wed Jul 01 00:00:00 EDT 2015 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.m115.648907· OSTI ID:1400316

Allen, Samantha J. ^[1]; Parthasarathy, Gopal ^[2]; Darke, Paul L. ^[1]; Diehl, Ronald E. ^[1]; Ford, Rachael E. ^[1]; Hall, Dawn L. ^[1]; Johnson, Scott A. ^[2]; Reid, John C. ^[2]; Rickert, Keith W. ^[1]; Shipman, Jennifer M. ^[1]; Soisson, Stephen M. ^[2]; Zuck, Paul ^[1]; Munshi, Sanjeev K. ^[1]; Lumb, Kevin J. ^[1]

Merck Research Laboratories, North Wales, PA (United States). Protein Sciences
Merck Research Laboratories, West Point, PA (United States). Structural Chemistry

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 Å structure of human GRK4α A486V crystallized in the presence of 5'-adenylyl β,γ-imidodiphosphate. The structure of GRK4α is similar to other GRKs, although slight differences exist within the RGS homology (RH) bundle subdomain, substrate-binding site, and kinase C-tail. The RH bundle subdomain and kinase C-terminal lobe form a strikingly acidic surface, whereas the kinase N-terminal lobe and RH terminal subdomain surfaces are much more basic. In this respect, GRK4α 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 αB helix, αD helix, and the P-loop. Autophosphorylation of wild-type GRK4α 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 GRK4α A486V. Phosphopeptide mapping by mass spectrometry indicates an increased rate of autophosphorylation of a number of residues in GRK4α A486V relative to wild-type GRK4α, including Ser-485 in the kinase C-tail.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1400316

Journal Information:: Journal of Biological Chemistry, Vol. 290, Issue 33; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 11 works

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59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
G-protein-coupled receptor (GPCR)
hypertension
kinetics
phosphorylation
serine/threonine protein kinase
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GRK4

Title: Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4

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