G protein-coupled receptor kinases (GRKs) play pivotal roles in the desensitization of G protein-coupled receptors (GPCRs) signaling. Mutations of GRKs are associated with a variety of diseases, such as heart failure, Parkinson’s disease and diabetes. 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), CAS made progresses in discovering the key components for the rhodopsin/ GRK1 interaction and provide a framework for understanding GRK-mediated desensitization of GPCRs. The finding has been published in the Cell Research.

GPCRs play fundamental roles in a broad spectrum of physiological processes and are involved in blood-related diseases. GRKs can deactivate GPCR signaling to maintain cellular homeostasis. The receptor is then recognized by arrestins, which block G-protein access and induce the internalization of the receptor-arrestin complex to shut down the signal transduction.

Researchers at SIMM, CAS used rhodopsin, an extensively studied receptor as a model for understanding GPCR-GRK signaling. The research 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.

Researchers also provided mechanistic understanding of how Q41L in GRK5, a well-established gain-of-function mutation, can fight against heart failure. Finally, researchers presented an overall architecture of the Rho/GRK complex assembly through single-particle reconstruction from negative stain electron microscopy (EM) images.

These findings in turn provide a framework for understanding the desensitization of GPCRs and generates 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.

Full text link: https://www.nature.com/cr/journal/vaop/ncurrent/full/cr201772a.html

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

Keywords: rhodopsin; GPCR; GRK1; GRK5; Q41L
Corresponding authors:
H. Eric Xu
Email: Eric.Xu@vai.org

(Credit: YIN Yanting)