title: Crystal structure of arrestin-3 reveals the basis of the difference in receptor binding between two non-visual subtypes.
abstract: Arrestins are multi-functional proteins that regulate signaling and trafficking of the majority of G protein-coupled receptors (GPCRs), as well as sub-cellular localization and activity of many other signaling proteins. We report the first crystal structure of arrestin-3, solved at 3.0 Å resolution. Arrestin-3 is an elongated two-domain molecule with overall fold and key inter-domain interactions that hold the free protein in the basal conformation similar to the other subtypes. Arrestin-3 is the least selective member of the family, binding a wide variety of GPCRs with high affinity and demonstrating lower preference for active phosphorylated forms of the receptors. In contrast to the other three arrestins, part of the receptor-binding surface in the arrestin-3 C-domain does not form a contiguous β-sheet, which is consistent with increased flexibility. By swapping the corresponding elements between arrestin-2 and arrestin-3 we show that the presence of this loose structure is correlated with reduced arrestin selectivity for activated receptors, consistent with a conformational change in this β-sheet upon receptor binding.
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Xuanzhi
authors.initials: X
authors.lastname: Zhan
authors.forename: Luis E
authors.initials: LE
authors.lastname: Gimenez
authors.forename: Vsevolod V
authors.initials: VV
authors.lastname: Gurevich
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Spiller
mesh_terms: D000818:Animals; D019390:Arrestins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002417:Cattle; D003460:Crystallization; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; C082333:arrestin3