Crystal structure of β-arrestin at 1.9 Å:: Possible mechanism of receptor binding and membrane translocation

Background: Arrestins are responsible for the desensitization of many sequence-divergent G protein-coupled receptors. They compete with G proteins for binding to activated phosphorylated receptors, initiate receptor internalization, and activate additional signaling pathways. Results: In order to understand the structural basis for receptor binding and arrestin's function as an adaptor molecule, we determined the X-ray crystal structure of two truncated forms of bovine beta -arrestin in its cytosolic inactive state to 1.9 Angstrom. Mutational analysis and chimera studies identify the regions in beta -arrestin responsible for receptor binding specificity. beta -arrestin demonstrates high structural homology with the previously solved visual arrestin. All key structural elements responsible for arrestin's mechanism of activation are conserved. Conclusions: Based on structural analysis and mutagenesis data, we propose a previously unappreciated part in beta -arrestin's mode of action by which a cationic amphipathic helix may function as a reversible membrane anchor. This novel activation mechanism would facilitate the formation of a high-affinity complex between beta -arrestin and an activated receptor regardless of its specific subtype. Like the interaction between beta -arrestin's polar core and the phosphorylated receptor, such a general activation mechanism would contribute to beta -arrestin's versatility as a regulator of many receptors.