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

• Published in: Structure (London) 2003-07, Vol.11 (7), p.845-853
• Main Authors: Kang, Beom Sik, Cooper, David R., Devedjiev, Yancho, Derewenda, Urszula, Derewenda, Zygmunt S.
• Format: Article
• Language: English
• Subjects: Carrier Proteins - chemistry; Carrier Proteins - metabolism; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins - metabolism; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Models, Molecular; Protein Binding; Protein Conformation; Proteoglycans - metabolism; Receptors, Interleukin - metabolism; Receptors, Interleukin-5; Serine - metabolism; Syndecans; Syntenins
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/S0969-2126(03)00125-4

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 (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 S 0 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.