Molecular assembly of rhodopsin with G protein-coupled receptor kinases

Cell Research
Yuanzheng HeH Eric Xu

Abstract

G protein-coupled receptor kinases (GRKs) play pivotal roles in desensitizing GPCR signaling but little is known about how GRKs recognize and phosphorylate GPCRs due to the technical difficulties in detecting the highly dynamic GPCR/GRK interaction. By combining a genetic approach with multiple biochemical assays, we identified the key determinants for the assembly of the prototypical GPCR rhodopsin with its kinase GRK1. Our work reveals 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. In addition, we provide a mechanistic solution for the longstanding puzzle about the gain-of-function Q41L mutation in GRK5. This mutation is in the RH domain and increases the capacity of the GRK mutant to interact with and to desensitize GPCRs. Finally we present the principal architecture of a rhodopsin/GRK complex through negative stain electron microscopy reconstruction. Together, these data define the key components for the rhodopsin/GRK1 interaction and provide a framework for understanding GRK-mediated desensitization of GPCRs.

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Citations

Dec 1, 2017·International Journal of Molecular Sciences·Vsevolod V Gurevich, Eugenia V Gurevich
Oct 13, 2018·Protein Science : a Publication of the Protein Society·X Edward ZhouH Eric Xu
Jan 13, 2018·Open Biology·Trevor D LambDavid M Hunt
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Oct 28, 2019·Bone Research·Jian LuoJianru Xiao
Aug 16, 2017·The Journal of Biological Chemistry·Xin-Qiu YaoBarry J Grant
Jul 6, 2018·Nature·David M ThalArthur Christopoulos
Mar 7, 2019·Frontiers in Pharmacology·Vsevolod V Gurevich, Eugenia V Gurevich
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Feb 10, 2021·Biomolecules·Mohammad SeyedabadiVsevolod V Gurevich
Mar 24, 2020·Pharmacology & Therapeutics·Vsevolod V Gurevich, Eugenia V Gurevich
Apr 11, 2018·Trends in Biochemical Sciences·Qiuyan ChenVsevolod V Gurevich
May 26, 2020·Pharmacology & Therapeutics·Bao-Chun JiangYong-Jing Gao
Mar 16, 2021·Current Opinion in Endocrine and Metabolic Research·Sarah M Sulon, Jeffrey L Benovic
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May 10, 2018·Trends in Pharmacological Sciences·Vsevolod V Gurevich, Eugenia V Gurevich
Jul 16, 2021·Nature·Vsevolod V Gurevich, Eugenia V Gurevich

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Methods Mentioned

BETA
electron microscopy
co-IP
pull-down
FRET
BRET
AlphaScreen
transfection
direct
kinase

Software Mentioned

AlphaScreen
RELION
EMAN
GraphPad Prism
Excel
Tango
EMAN2

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