Molecular Roots of Degenerate Specificity in Syntenin's PDZ2 Domain Reassessment of the PDZ Recognition Paradigm

AbstractCrystal structures of the PDZ2 domain of the scaffolding protein syntenin, both unbound and in complexes with peptides derived from C termini of IL5 receptor (α chain) and syndecan, reveal the molecular roots of syntenin's degenerate specificity. Three distinct binding sites (S0, S−1, and S−2), with affinities for hydrophobic side chains, function in a combinatorial way: S−1 and S−2 act together to bind syndecan, while S0 and S−1 are involved in the binding of IL5Rα. Neither mode of interaction is consistent with the prior classification scheme, which defined the IL5Rα interaction as class I (-S/T-X-φ) and the syndecan interaction as class II (-φ-X-φ). These results, in conjunction with other emerging structural data on PDZ domains, call for a revision of their classification and of the existing model of their mechanism