The Structure of the Tiam1 PDZ Domain/ Phospho-Syndecan1 Complex Reveals a Ligand Conformation that Modulates Protein Dynamics

• Published in: Structure (London) 2013-03, Vol.21 (3), p.342-354
• Main Authors: Liu, Xu, Shepherd, Tyson R., Murray, Ann M., Xu, Zhen, Fuentes, Ernesto J.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Binding Sites; Computer Simulation; Crystal structure; Crystallography, X-Ray; Decoupling; Dynamics; Guanine Nucleotide Exchange Factors - chemistry; Humans; Ligands; Models, Molecular; Molecular Sequence Data; PDZ Domains; Phosphorylation; Pocket; Protein Binding; Protein Structure, Secondary; Proteins; Structure-Activity Relationship; Syndecan-1 - chemistry; Syndecan-2 - chemistry; Syndecan-3 - chemistry; Syndecan-4 - chemistry; T-Lymphoma Invasion and Metastasis-inducing Protein 1
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2013.01.004

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. [Display omitted] ► The Tiam1 PDZ domain preferentially binds a subset of syndecan (SDC) proteins ► The PDZ domain/phospho-SDC1 structure reveals a phosphoryl binding pocket ► Ligand specificity and phosphorylation regulate PDZ/SDC interactions and signaling ► Tiam1 PDZ domain dynamics are ligand-dependent and regulated by phosphorylation Liu et al. solve structures of the Tiam1 PDZ domain bound to syndecan1 and phophosyndecan1 peptides. The structures and NMR relaxation experiments reveal a unique phosphoryl pocket and show that phosphoryl interactions dampen motions in distal regions of the PDZ domain, decoupling them from the ligand-binding site.