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GRK2 Activation By Receptors
Author(s) -
SterneMarr Rachel,
Leahey Alex,
Amie Sarah M,
Donnelly Ryan,
Lopez Thomas S,
Tesmer John J
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.855.8
Subject(s) - beta adrenergic receptor kinase , g protein coupled receptor kinase , g protein coupled receptor , receptor , agonist , kinase , microbiology and biotechnology , phosphorylation , rhodopsin , rhodopsin like receptors , protein kinase domain , biology , chemistry , biochemistry , mutant , metabotropic receptor , retinal , gene
G protein‐coupled receptor (GPCR) kinases (GRKs) were identified by their ability to phosphorylate activated GPCRs. They constitute a branch of the AGC kinase superfamily and are activated by hormone‐treated receptors. Their mechanism of activation is largely unknown; thus, we initiated a study to identify GRK2 residues involved in interactions with their substrate receptors. Our study focused on the kinase large lobe and an extension of the kinase domain known as the C‐tail. Four substitutions, all within or adjacent to the C‐tail, resulted a decrease in the ability of GRK2 to phosphorylate activated GPCRs, rhodopsin and the beta‐adrenergic receptor. The mutant exhibiting the most dramatic impairment, V477D, also showed significant defects in phosphorylation of non‐receptor substrates. V477D had 12‐fold lower turnover number and was resistant to activation by agonist‐treated beta‐adrenergic receptor. Therefore, Val477 and other residues in the C‐tail are expected to play a role in the activation of GRK2 by GPCRs. Current studies focus on other regions of GRK2 required for receptor binding and activation. NSF Grants MCB0315888 and MCB0744739 to R.S.‐M. and NIH Grants HL086865 and HL071818 and American Heart Association Scientist Development Grant 0235273N to J.J.G.T.