The structure of the Tiam1 PDZ domain/ phospho-syndecan1 complex reveals a ligand conformation that modulates protein dynamics

Structure. 2013 Mar 5;21(3):342-54. doi: 10.1016/j.str.2013.01.004. Epub 2013 Feb 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Guanine Nucleotide Exchange Factors / chemistry*
  • Humans
  • Ligands
  • Models, Molecular*
  • Molecular Sequence Data
  • PDZ Domains
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Secondary
  • Structure-Activity Relationship
  • Syndecan-1 / chemistry*
  • Syndecan-2 / chemistry
  • Syndecan-3 / chemistry
  • Syndecan-4 / chemistry
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1


  • Guanine Nucleotide Exchange Factors
  • Ligands
  • SDC1 protein, human
  • SDC2 protein, human
  • SDC3 protein, human
  • SDC4 protein, human
  • Syndecan-1
  • Syndecan-3
  • Syndecan-4
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • TIAM1 protein, human
  • Syndecan-2

Associated data

  • PDB/4GVC
  • PDB/4GVD