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Vol. 20, Issue 5, 1324-1339, March 1, 2009

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The E3 Ubiquitin Ligase Atrophin Interacting Protein 4 Binds Directly To The Chemokine Receptor CXCR4 Via a Novel WW Domain-mediated Interaction

Deepali Bhandari^*, Seth L. Robia, and Adriano Marchese^*,

Departments of Pharmacology and Experimental Therapeutics and Cell and Molecular Physiology and *Program in Molecular Biology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153

Submitted March 21, 2008; Revised November 25, 2008; Accepted December 19, 2008
Monitoring Editor: Thomas Sommer

The E3 ubiquitin ligase atrophin interacting protein 4 (AIP4) mediates ubiquitination and down-regulation of the chemokine receptor CXCR4. AIP4 belongs to the Nedd4-like homologous to E6-AP carboxy terminus domain family of E3 ubiquitin ligases, which typically bind proline-rich motifs within target proteins via the WW domains. The intracellular domains of CXCR4 lack canonical WW domain binding motifs; thus, whether AIP4 is targeted to CXCR4 directly or indirectly via an adaptor protein remains unknown. Here, we show that AIP4 can interact directly with CXCR4 via a novel noncanonical WW domain-mediated interaction involving serine residues 324 and 325 within the carboxy-terminal tail of CXCR4. These serine residues are critical for mediating agonist-promoted binding of AIP4 and subsequent ubiquitination and degradation of CXCR4. These residues are phosphorylated upon agonist activation and phosphomimetic mutants show enhanced binding to AIP4, suggesting a mechanism whereby phosphorylation mediates the interaction between CXCR4 and AIP4. Our data reveal a novel noncanonical WW domain-mediated interaction involving phosphorylated serine residues in the absence of any proline residues and suggest a novel mechanism whereby an E3 ubiquitin ligase is targeted directly to an activated G protein-coupled receptor.

Address correspondence to: Adriano Marchese (amarchese{at}lumc.edu)

Abbreviations used: AIP4, atrophin-interacting protein 4; FRET, fluorescence resonance energy transfer; GPCR, G protein-coupled receptor; GST, glutathione transferase; HECT, homologous to E6-AP carboxy terminus; TIRF, total internal reflection fluorescence.

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