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

Molecular Biology of the Cell - Tập 20 Số 5 - Trang 1324-1339 - 2009
Deepali Bhandari1, Seth L. Robia2, Adriano Marchese3,4
1Program in Molecular Biology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
2Cell and Molecular Physiology and
3*Program in Molecular Biology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153
4Departments of Pharmacology and Experimental Therapeutics and

Tóm tắt

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.

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Thông tin xuất bản

Molecular Biology of the Cell

Tập 20 Số 5

1324-1339

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