☆ 4.8 Article

Structure of a GRK5-Calmodulin Complex Reveals Molecular Mechanism of GRK Activation and Substrate Targeting

MOLECULAR CELL (2021)

Journal

MOLECULAR CELL

Volume 81, Issue 2, Pages 323-+

Publisher

CELL PRESS

DOI: 10.1016/j.molcel.2020.11.026

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Funding

NIH [R35GM122541, R01HL142310, R01GM104047, R01GM127359]
National Research Foundation of Korea - Korean government [NFR-2019R1A5A2027340, NRF-2018R1A2B6001554]
National Research Foundation of Korea [4120200813689] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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Abstract

In this study, the complex of CaM with GRK5 was analyzed structurally, computationally, and biochemically to reveal how CaM modulates GRK5 response to calcium, leading to activation and localization effects for selective substrate targeting by GRK5.

The phosphorylation of G protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) facilitates arrestin binding and receptor desensitization. Although this process can be regulated by Ca2+-binding proteins such as calmodulin (CaM) and recoverin, the molecular mechanisms are poorly understood. Here, we report structural, computational, and biochemical analysis of a CaM complex with GRK5, revealing how CaM shapes GRK5 response to calcium. The CaM N and C domains bind independently to two helical regions at the GRK5 N and C termini to inhibit GPCR phosphorylation, though only the C domain interaction disrupts GRK5 membrane association, thereby facilitating cytoplasmic translocation. The CaM N domain strongly activates GRK5 via ordering of the amphipathic alpha N-helix of GRK5 and allosteric disruption of kinase-RH domain interaction for phosphorylation of cytoplasmic GRK5 substrates. These results provide a framework for understanding how two functional effects, GRK5 activation and localization, can cooperate under control of CaM for selective substrate targeting by GRK5.

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Heterotrimeric Gq proteins act as a switch for GRK5/6 selectivity underlying β-arrestin transducer bias

Kouki Kawakami, Masataka Yanagawa, Suzune Hiratsuka, Misaki Yoshida, Yuki Ono, Michio Hiroshima, Masahiro Ueda, Junken Aoki, Yasushi Sako, Asuka Inoue

Summary: This study uncovers the role of Gq heterotrimer in determining GRK subtype selectivity, which in turn regulates the conformation and functionality of β-arrestin. By investigating the angiotensin II type-1 receptor, the authors find that both GRK2/3 and GRK5/6 are recruited by Ang II, while only GRK5/6 is recruited by the β-arrestin-biased ligand TRV027. Additionally, inhibition of Gq shifts the GRK subtype selectivity and β-arrestin functionality to that of TRV027.

NATURE COMMUNICATIONS (2022)