Frizzled 7 and PIP2 binding by syntenin PDZ2 domain supports Frizzled 7 trafficking and signalling

• DOI: 10.1038/ncomms12101
• Publication Date: 2016-07-08T09:05:20Z
• Authors: Antonio Luis Egea...; Rodrigo Gallardo; Abel Garcia-Pino; Ylva Ivarsson; Anna Maria Wawrzy...; Rudra Kashyap; Remy Loris; Joost Schymkowitz; Frederic Rousseau; Pascale Zimmermann
• Keywords: Models, Molecular; Phosphatidylinositol 4,5-Diphosphate; Protein Conformation, alpha-Helical; 0301 basic medicine; Syntenins; [SDV]Life Sciences [q-bio]; Science; Genetic Vectors; Gene Expression; PDZ Domains; Membrane trafficking; Crystallography, X-Ray; Article; Membrane biophysics; 03 medical and health sciences; G protein-coupled receptors; Structural Biology; molecular biophysics; structural biology; Humans; Protein Interaction Domains and Motifs; Cloning, Molecular; Strukturbiologi; Binding Sites; Q; Sciences bio-médicales et agricoles; Frizzled Receptors; Recombinant Proteins; [SDV] Life Sciences [q-bio]; Protein Transport; MCF-7 Cells; Protein Conformation, beta-Strand; Cell signalling; Protein Binding; Signal Transduction

AbstractPDZ domain-containing proteins work as intracellular scaffolds to control spatio-temporal aspects of cell signalling. This function is supported by the ability of their PDZ domains to bind other proteins such as receptors, but also phosphoinositide lipids important for membrane trafficking. Here we report a crystal structure of the syntenin PDZ tandem in complex with the carboxy-terminal fragment of Frizzled 7 and phosphatidylinositol 4,5-bisphosphate (PIP2). The crystal structure reveals a tripartite interaction formed via the second PDZ domain of syntenin. Biophysical and biochemical experiments establish co-operative binding of the tripartite complex and identify residues crucial for membrane PIP2-specific recognition. Experiments with cells support the importance of the syntenin–PIP2 interaction for plasma membrane targeting of Frizzled 7 and c-jun phosphorylation. This study contributes to our understanding of the biology of PDZ proteins as key players in membrane compartmentalization and dynamics.