Substrate-Induced Changes in the Dynamics of Rhodopsin Kinase (G Protein-Coupled Receptor Kinase 1)
2012
Orban, Tivadar | Huang, Chih-chin | Homan, Kristoff T. | Jastrzębska, Beata | Tesmer, John J. G. | Palczewski, Krzysztof
G protein-coupled receptor (GPCR) kinases (GRKs) instigate the desensitization of activated GPCRs via phosphorylation that promotes interaction with arrestins, thereby preventing the interaction of GPCRs with heterotrimeric G proteins. A current proposed model of GRK1 activation involves the binding of activated rhodopsin (Rho*) to the N-terminal region of GRK1. Perhaps concomitantly, this N-terminal region also stabilizes a closed, active conformation of the kinase domain. To further probe this model, we mapped changes in the backbone flexibility of GRK1 as it binds to its two substrates, adenosine triphosphate (Mg²⁺·ATP) and Rho*. We found that the conformational flexibility of GRK1 was reduced in the presence of either Mg²⁺·ATP or Rho*, with Mg²⁺·ATP having the greatest effect. In a truncated form of GRK1 lacking the N-terminal region (ΔN-GRK1), peptides that directly interact with ATP were not as dramatically stabilized by adding Mg²⁺·ATP, and dynamics were greater in the interface between the large lobe of the kinase domain and the regulator of the G protein signaling homology domain. In the presence of Mg²⁺·ATP, the influence of Rho* versus Rho on GRK1 dynamics was negligible.
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