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.
Kang, B. S., Cooper, D. R., Devedjiev, Y., Derewenda, U., & Derewenda, Z. S. (2003). Molecular roots of degenerate specificity in syntenin’s PDZ2 domain: Reassessment of the PDZ recognition paradigm. Structure, 11(7), 845–853. https://doi.org/10.1016/S0969-2126(03)00125-4