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

卷:12

Article

关键词: MUSCARINIC ACETYLCHOLINE-RECEPTOR;    PROTEIN-COUPLED RECEPTORS;    3RD INTRACELLULAR LOOP;    CRYSTAL-STRUCTURE;    BETA-ARRESTIN;    VISUAL ARRESTIN;    PHOSPHORYLATION SITES;    CLATHRIN ADAPTER;    48-KDA PROTEIN;    RHODOPSIN;   

DOI  :  10.3390/cells12121563

来源: SCIE

【 摘 要 】

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.