| Abstract
| - PDZ domains are among the most abundant protein modules in the known genomes. Theirmain function is to provide scaffolds for membrane-associated protein complexes by binding to the cytosolic,C-terminal fragments of receptors, channels, and other integral membrane proteins. Here, using bothheteronuclear NMR and single crystal X-ray diffraction, we show how peptides with different sequences,including those corresponding to the C-termini of syndecan, neurexin, and ephrin B, can simultaneouslybind to both PDZ domains of the scaffolding protein syntenin. The PDZ2 domain binds these peptides inthe canonical fashion, and an induced fit mechanism allows for the accommodation of a range of sidechains in the P0 and P-2 positions. However, binding to the PDZ1 domain requires that the target peptideassume a noncanonical conformation. These data help explain how syntenin, and perhaps other PDZ-containing proteins, may preferentially bind to dimeric and clustered targets, and provide a mechanisticexplanation for the previously reported cooperative ligand binding by syntenin's two PDZ domains.
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