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Science's STKE  18 Dec 2007:
Vol. 2007, Issue 417, pp. tw456
DOI: 10.1126/stke.4172007tw456

Polarization of various cell types depends on a complex containing the PDZ domain-containing scaffolding proteins Par-3 and Par-6 and atypical protein kinase C. Noting that phosphoinositides (PIPs) have also been implicated in cell polarization and that PDZ domains--although better known for mediating protein-protein interactions--can bind phosphatidylinositol (PI) lipids, Wu et al. investigated interactions between Par protein PDZ domains and PI lipids. The second Par-3 PDZ domain (PDZ2) bound to brain-derived liposomes with an affinity comparable to that of the PLCδ pleckstrin homology (PH) domain (a PI lipid-binding domain); strip-based assays and experiments with defined liposomes indicated that it bound directly to PIPs. Lipid-binding assays of 74 human PDZ domains and 14 PDZ tandems revealed that a subset bound PI lipids. Structural and biochemical analysis indicated that lipid binding by the Par-3 PDZ2 depended on a cluster of positively charged residues and that PDZ2 contained a PIP head group-binding pocket that overlapped its peptide ligand-binding site. In MDCK epithelial cells, Par-3 primarily localized to the cell membrane; mutational analysis indicated that membrane localization depended on PI lipid binding by PDZ2. Par-3 knockdown disrupted tight junction formation and reestablishment of polarization in MDCK cells. Epithelial repolarization was rescued by wild-type Par-3 or by a mutant in which the PLCδ PH domain replaced PDZ2 but not by mutants defective in lipid binding. The Par-3 PDZ3 domain bound to the lipid phosphatase PTEN. The authors conclude that lipid binding by the Par-3 PDZ2 domain is critical to its role in epithelial polarization and that the combination of PIP-binding by PDZ2 and PTEN-binding by PDZ3 could enable Par-3 to integrate PIP signaling.

H. Wu, W. Feng, J. Chen, L.-N. Chan, S. Huang, M. Zhang, PDZ domains of Par-3 as potential phosphoinositide signaling integrators. Mol. Cell 28, 886-898 (2007). [PubMed]

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