GPCR Binding and JNK3 Activation by Arrestin-3 Have Different Structural Requirements.

Chen Zheng, Liana D Weinstein, Kevin K Nguyen, Abhijeet Grewal, Eugenia V Gurevich, Vsevolod V Gurevich

Cells 2023 Jun 06

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Arrestins bind active phosphorylated G protein-coupled receptors (GPCRs). Among the four mammalian subtypes, only arrestin-3 facilitates the activation of JNK3 in cells. In available structures, Lys-295 in the lariat loop of arrestin-3 and its homologue Lys-294 in arrestin-2 directly interact with the activator-attached phosphates. We compared the roles of arrestin-3 conformational equilibrium and Lys-295 in GPCR binding and JNK3 activation. Several mutants with enhanced ability to bind GPCRs showed much lower activity towards JNK3, whereas a mutant that does not bind GPCRs was more active. The subcellular distribution of mutants did not correlate with GPCR recruitment or JNK3 activation. Charge neutralization and reversal mutations of Lys-295 differentially affected receptor binding on different backgrounds but had virtually no effect on JNK3 activation. Thus, GPCR binding and arrestin-3-assisted JNK3 activation have distinct structural requirements, suggesting that facilitation of JNK3 activation is the function of arrestin-3 that is not bound to a GPCR.

Citation

Chen Zheng, Liana D Weinstein, Kevin K Nguyen, Abhijeet Grewal, Eugenia V Gurevich, Vsevolod V Gurevich. GPCR Binding and JNK3 Activation by Arrestin-3 Have Different Structural Requirements. Cells. 2023 Jun 06;12(12)