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Scientists Reveal How G protein-coupled Receptor Kinases Recognize and Phosphorylate G protein-coupled Receptors

Jun 21, 2017

G protein-coupled receptor kinases (GRKs) play pivotal roles in the desensitization of G protein-coupled receptors (GPCRs) signaling. It can deactivate GPCR signaling to maintain cellular homeostasis. However, so far, little is known about how GRKs recognize and phosphorylate GPCRs due to the weak and transient interaction between receptor and GRK.

Scientists from Shanghai Institute of Materia Medica (SIMM) of Chinese Academy of Sciences made progress in discovering the key components for the rhodopsin/ GRK1 interaction and provided a framework to understand GRK-mediated desensitization of GPCRs. This study has been published in the Cell Research.

Researchers used rhodopsin, an extensively studied receptor as a model to understand GPCR-GRK signaling. They revealed that the regulatory G-protein signaling homology (RH) domain of GRKs is the primary binding site to GPCRs and an active conformation of the GRK1 kinase domain is required for efficient interaction with rhodopsin.

Mechanistic solution to how Q41L in GRK5, a well-established gain-of-function mutation, can fight against heart failure was then proposed by researchers. Besides, they presented an overall architecture of the Rho/GRK complex assembly through single-particle reconstruction from negative stain electron microscopy (EM) images.

These findings provided a framework to understand the desensitization of GPCRs and generated insightful information for future high-resolution structure determination of a GPCR/GRK complex.

This work was supported by the Ministry of Science and Technology grants, the National Institute of Health grants, American Asthma Foundation, Jay and Betty Van Andel Foundation, the Van Andel Research Institute Cryo-EM core facility, the Canada Excellence Research Chairs program and the Anne and Max Tanenbaum Chair in Neuroscience to OPE.

 

 Figure: Negative stain EM reveals the principal architecture of the rhodopsin/GRK5 complex. (Image by Van Andel Research Institute) 

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