Molecular roots of degenerate specificity in syntenin's PDZ2 domain: Reassessment of the PDZ recognition paradigm

Crystal 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.