Critical role of the central 139-loop in stability and binding selectivity of arrestin-1.

Vishnivetskiy SA, Baameur F, Findley KR, Gurevich VV
J Biol Chem. 2013 288 (17): 11741-50

PMID: 23476014 · PMCID: PMC3636863 · DOI:10.1074/jbc.M113.450031

Arrestin-1 selectively binds active phosphorylated rhodopsin (P-Rh*), demonstrating much lower affinity for inactive phosphorylated (P-Rh) and unphosphorylated active (Rh*) forms. Receptor interaction induces significant conformational changes in arrestin-1, which include large movement of the previously neglected 139-loop in the center of the receptor binding surface, away from the incoming receptor. To elucidate the functional role of this loop, in mouse arrestin-1 we introduced deletions of variable lengths and made several substitutions of Lys-142 in it and Asp-72 in the adjacent loop. Several mutants with perturbations in the 139-loop demonstrate increased binding to P-Rh*, dark P-Rh, Rh*, and phospho-opsin. Enhanced binding of arrestin-1 mutants to non-preferred forms of rhodopsin correlates with decreased thermal stability. The 139-loop perturbations increase P-Rh* binding of arrestin-1 at low temperatures and further change its binding profile on the background of 3A mutant, where the C-tail is detached from the body of the molecule by triple alanine substitution. Thus, the 139-loop stabilizes basal conformation of arrestin-1 and acts as a brake, preventing its binding to non-preferred forms of rhodopsin. Conservation of this loop in other subtypes suggests that it has the same function in all members of the arrestin family.

MeSH Terms (14)

Amino Acid Substitution Animals Arrestins beta-Arrestins Binding Sites Cattle Humans Mice Mutation, Missense Protein Binding Protein Stability Protein Structure, Secondary Rats Rod Opsins

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