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J. Biol. Chem., Vol. 282, Issue 26, 18937-18944, June 29, 2007

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N-terminal Tyrosine Modulation of the Endocytic Adaptor Function of the -Arrestins^*

From the Department of Cell Biology, Duke University, Durham, North Carolina 27710

The highly homologous -arrestin1 and -2 adaptor proteins play important roles in the function of G protein-coupled receptors. Either -arrestin variant can function as a molecular chaperone for clathrin-mediated receptor internalization. This role depends primarily upon two distinct, contiguous C-terminal -arrestin motifs recognizing clathrin and the -adaptin subunit of AP2. However, a molecular basis is lacking to explain the different endocytic efficacies of the two -arrestin isoforms and the observation that -arrestin N-terminal substitution mutants can act as dominant negative inhibitors of receptor endocytosis. Despite the near identity of the -arrestins throughout their N termini, sequence variability is present at a small number of residues and includes tyrosine to phenylalanine substitutions. Here we show that corresponding N-terminal (Y/F)VTL sequences in -arrestin1 and -2 differentially regulate µ-adaptin binding. Our results indicate that the -arrestin1 Tyr-54 lessens the interaction with µ-adaptin and moreover is a Src phosphorylation site. A gain of endocytic function is obtained with the -arrestin1 Y54F substitution, which improves both the -arrestin1 interaction with µ-adaptin and the ability to enhance 2-adrenergic receptor internalization. These data indicate that -arrestin2 utilizes µ-adaptin as an endocytic partner, and that the inability of -arrestin1 to sustain a similar degree of interaction with µ-adaptin may result from coordination of Tyr-54 by neighboring residues or its modification by Src kinase. Additionally, these naturally occurring variations in -arrestins may also differentially regulate the composition of the signaling complexes organized on the receptor.

Received for publication, January 4, 2007 , and in revised form, April 13, 2007.

^* This work was supported by the National Institutes of Health Grants GM 069086 (to G. B. F.), HL 61365 (to L. S. B.), and NS 19576 (to M. G. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Recipient of a fellowship from the Medical Research Council of Canada. Present address: Department of Endocrinology, McGill University, Montreal, H3A 1A1 Canada.

³ To whom correspondence may be addressed: Box 3287, Duke University, Durham, NC 27710. Tel.: 919-684-5433; Fax: 919-681-8641; E-mail: m.caron{at}cellbio.duke.edu. ⁴ To whom correspondence may be addressed: Box 3287, Duke University, Durham, NC 27710. Tel.: 919-684-6245; Fax: 919-681-8641; E-mail: l.barak{at}cellbio.duke.edu.

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