title: The structure of the Tiam1 PDZ domain/ phospho-syndecan1 complex reveals a ligand conformation that modulates protein dynamics.
abstract: PDZ (PSD-95/Dlg/ZO-1) domains are protein-protein interaction modules often regulated by ligand phosphorylation. Here, we investigated the specificity, structure, and dynamics of Tiam1 PDZ domain/ligand interactions. We show that the PDZ domain specifically binds syndecan1 (SDC1), phosphorylated SDC1 (pSDC1), and SDC3 but not other syndecan isoforms. The crystal structure of the PDZ/SDC1 complex indicates that syndecan affinity is derived from amino acids beyond the four C-terminal residues. Remarkably, the crystal structure of the PDZ/pSDC1 complex reveals a binding pocket that accommodates the phosphoryl group. Methyl relaxation experiments of PDZ/SCD1 and PDZ/pSDC1 complexes reveal that PDZ-phosphoryl interactions dampen dynamic motions in a distal region of the PDZ domain by decoupling them from the ligand-binding site. Our data are consistent with a selection model by which specificity and phosphorylation regulate PDZ/syndecan interactions and signaling events. Importantly, our relaxation data demonstrate that PDZ/phospho-ligand interactions regulate protein dynamics and their coupling to distal sites.
authors: Department of Biochemistry, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA.
authors: Xu
authors: X
authors: Liu
authors: Tyson R
authors: TR
authors: Shepherd
authors: Ann M
authors: AM
authors: Murray
authors: Zhen
authors: Z
authors: Xu
authors: Ernesto J
authors: EJ
authors: Fuentes
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054731:PDZ Domains; D010766:Phosphorylation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D053668:Syndecan-1 / Q000737:chemistry*; D053669:Syndecan-2 / Q000737:chemistry; D053670:Syndecan-3 / Q000737:chemistry; D053671:Syndecan-4 / Q000737:chemistry; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D008024:Ligands; C508241:SDC1 protein, human; C508245:SDC2 protein, human; C508301:SDC3 protein, human; C508304:SDC4 protein, human; D053668:Syndecan-1; D053670:Syndecan-3; D053671:Syndecan-4; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D053669:Syndecan-2
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