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 (alpha chain) and synclecan, reveal the molecular roots of syntenin's degenerate specificity. Three distinct binding sites (S-0, 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 So and S-1 are involved in the binding of IL5Ralpha. Neither mode of interaction is consistent with the prior classification scheme, which defined the IL5Ralpha interaction as class I (-S/T-X-phi) and the syndecan interaction as class II (-phi-X-phi). 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.