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Cone arrestin binding to JNK3 and Mdm2: conformational preference and localization of interaction sites

Arrestins are multi‐functional regulators of G protein‐coupled receptors. Receptor‐bound arrestins interact with >30 remarkably diverse proteins and redirect the signaling to G protein‐independent pathways. The functions of free arrestins are poorly understood, and the interaction sites of the non‐receptor arrestin partners are largely unknown. In this study, we show that cone arrestin, the least studied member of the family, binds c‐Jun N‐terminal kinase (JNK3) and Mdm2 and regulates their subcellular distribution. Using arrestin mutants with increased or reduced structural flexibility, we demonstrate that arrestin in all conformations binds JNK3 comparably, whereas Mdm2 preferentially binds cone arrestin ‘frozen’ in the basal state. To localize the interaction sites, we expressed separate N‐ and C‐domains of cone and rod arrestins and found that individual domains bind JNK3 and remove it from the nucleus as efficiently as full‐length proteins. Thus, the arrestin binding site for JNK3 includes elements in both domains with the affinity of partial sites on individual domains sufficient for JNK3 relocalization. N‐domain of rod arrestin binds Mdm2, which localizes its main interaction site to this region. Comparable binding of JNK3 and Mdm2 to four arrestin subtypes allowed us to identify conserved residues likely involved in these interactions.