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

Autor:	Komolov KE; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA., Sulon SM; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA., Bhardwaj A; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA., van Keulen SC; Department of Computer Science, Department of Molecular and Cellular Physiology, Department of Structural Biology, and Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA., Duc NM; School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea; Division of Precision Medicine, Research Institute, National Cancer Center, Goyang, South Korea., Laurinavichyute DK; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA., Lou HJ; Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA., Turk BE; Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA., Chung KY; School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea., Dror RO; Department of Computer Science, Department of Molecular and Cellular Physiology, Department of Structural Biology, and Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA; Biophysics Program, Stanford University, Stanford, CA 94305, USA., Benovic JL; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: jeffrey.benovic@jefferson.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2021 Jan 21; Vol. 81 (2), pp. 323-339.e11. Date of Electronic Publication: 2020 Dec 14.
DOI:	10.1016/j.molcel.2020.11.026
Abstrakt:	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 Ca 2+ -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 αN-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. Competing Interests: Declaration of Interests The authors declare no competing interests. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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