Structure
Volume 9, Issue 9, September 2001, Pages 869-880
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Article
Crystal Structure of β-Arrestin at 1.9 Å: Possible Mechanism of Receptor Binding and Membrane Translocation

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Abstract

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 β-arrestin in its cytosolic inactive state to 1.9 Å. Mutational analysis and chimera studies identify the regions in β-arrestin responsible for receptor binding specificity. β-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 β-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 β-arrestin and an activated receptor regardless of its specific subtype. Like the interaction between β-arrestin's polar core and the phosphorylated receptor, such a general activation mechanism would contribute to β-arrestin's versatility as a regulator of many receptors.

Keywords

arrestin
X-ray crystallography
GPCR
signal transduction
membrane proteins

Cited by (0)

4

Correspondence: Carsten Schubert; e-mail: [email protected]

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These authors contributed equally to this work.

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Present address: Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, Massachusetts 02139.

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Present address: 3-Dimensional-Pharmaceuticals Inc., 665 Stockton Drive, Exton, Pennsylvania 19341.