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• W4377029641 abstract "<b>Abstract ID 24257</b> <b>Poster Board 285</b> Changes in intracellular calcium regulate a variety of cellular processes including G protein-coupled receptor (GPCR) desensitization mediated by GPCR kinases (GRKs). At elevated calcium, Ca²⁺-binding proteins like calmodulin (CaM) and recoverin (Rec) target GRKs to terminate GRK-mediated phosphorylation of GPCRs at the plasma membrane and facilitate restoration of basal conditions in the cell. Recently, we demonstrated that calcium regulation of GRKs is more complex than merely inhibition of GPCR phosphorylation. For example, GRK5 can translocate to the cytoplasm and phosphorylate additional substrates in response to Ca²⁺/calmodulin binding. Strong activation of GRK5 through CaM-assisted ordering of the amphipathic aN-helix of GRK5 and allosteric disruption of kinase-RH domain interaction promotes GRK5-mediated phosphorylation of cytoplasmic substrates. Here, we addressed whether other members of the GRK family can be regulated in a similar manner. Despite Rec and CaM binding to the alphaN-helix of GRK1 and GRK6, respectively, this doesn’t induce strong enzyme activation as was observed in GRK5. Both complexes also lack additional high-affinity C-terminal binding sites leading to relatively low affinity of the interaction. We found that the C-terminal binding site is critical for stable association of CaM with GRK5 and its truncation promotes dissociation of the complex. Moreover, the specific geometry of the C-terminus in GRK5 is supported by a C-terminal kink enabling close proximity of N- and C-terminal sites for bipartite interface within CaM-GRK5 complex, thereby contributing to high-affinity binding and strong activation of GRK5. We also found that CaM coupling to GRK5 is independent of its conformation since CaM binding is equally strong when GRK5 is locked in an inactive conformation or preactivated by disruption of an electrostatic contact between the RH and catalytic domains. Together, our data support evolution of calcium regulation across the GRK family from simple modulation of GPCR phosphorylation at the plasma membrane (GRK1 and GRK6) to broad effects on GRK localization, activity and substrate specificity (GRK5)." @default.
• W4377029641 created "2023-05-19" @default.
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• W4377029641 date "2023-05-18" @default.
• W4377029641 modified "2023-09-29" @default.
• W4377029641 title "Calcium-dependent regulation of G protein-coupled receptor kinases" @default.
• W4377029641 doi "https://doi.org/10.1124/jpet.122.242570" @default.
• W4377029641 hasPublicationYear "2023" @default.
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