title: Molecular roots of degenerate specificity in syntenin's PDZ2 domain: reassessment of the PDZ recognition paradigm.
abstract: 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 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 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.
authors.affiliation: Department of Molecular Physiology and Biological Physics, The Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Beom Sik
authors.initials: BS
authors.lastname: Kang
authors.forename: David R
authors.initials: DR
authors.lastname: Cooper
authors.forename: Yancho
authors.initials: Y
authors.lastname: Devedjiev
authors.forename: Urszula
authors.initials: U
authors.lastname: Derewenda
authors.forename: Zygmunt S
authors.initials: ZS
authors.lastname: Derewenda
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011509:Proteoglycans / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D053649:Receptors, Interleukin-5; D012694:Serine / Q000378:metabolism; D053667:Syndecans; D053676:Syntenins
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011509:Proteoglycans; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; C109621:SDCBP protein, human; D053667:Syndecans; D053676:Syntenins; D012694:Serine