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 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.
Kang
Beom Sik
BS
Department of Molecular Physiology and Biological Physics, The Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
Cooper
David R
DR
Devedjiev
Yancho
Y
Derewenda
Urszula
U
Derewenda
Zygmunt S
ZS
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
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