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

Antonio Luis Egea-Jimenez, Rodrigo Gallardo, Abel Garcia-Pino, Ylva Ivarsson, Anna Maria Wawrzyniak, Rudra Kashyap, Remy Loris, Joost Schymkowitz, Frederic Rousseau and Pascale Zimmermann ()
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Antonio Luis Egea-Jimenez: Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes
Rodrigo Gallardo: KU Leuven
Abel Garcia-Pino: Structural Biology Brussels, Deptartment of Biotechnology (DBIT), Vrije Universiteit Brussel and Molecular Recognition Unit, Structural Biology Research Center
Ylva Ivarsson: KU Leuven
Anna Maria Wawrzyniak: KU Leuven
Rudra Kashyap: Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes
Remy Loris: Structural Biology Brussels, Deptartment of Biotechnology (DBIT), Vrije Universiteit Brussel and Molecular Recognition Unit, Structural Biology Research Center
Joost Schymkowitz: VIB Switch Laboratory
Frederic Rousseau: VIB Switch Laboratory
Pascale Zimmermann: Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12101

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