|Title||Frizzled 7 and PIP2 binding by syntenin PDZ2 domain supports Frizzled 7 trafficking and signalling.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Egea-Jimenez, A. Luis, R. Gallardo, A. Garcia-Pino, Y. Ivarsson, A. Maria Wawrzyniak, R. Kashyap, R. Loris, J. Schymkowitz, F. Rousseau, and P. Zimmermann|
|Date Published||2016 07 08|
|Keywords||Binding Sites, Cloning, Molecular, Crystallography, X-Ray, Frizzled Receptors, Gene Expression, Genetic Vectors, Humans, MCF-7 Cells, Models, Molecular, PDZ Domains, Phosphatidylinositol 4,5-Diphosphate, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protein Transport, Recombinant Proteins, Signal Transduction, Syntenins|
PDZ 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.
|Alternate Journal||Nat Commun|
|PubMed Central ID||PMC5515355|
|Grant List||647458 / / European Research Council / International|
Frizzled 7 and PIP2 binding by syntenin PDZ2 domain supports Frizzled 7 trafficking and signalling.