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

Antonio Luis Egea-Jimenez (1, 2) , Rodrigo Gallardo (2) , Abel Garcia-Pino (3) , Ylva Ivarsson (2) , Anna Maria Wawrzyniak (2) , Rudra Kashyap (1, 2) , Remy Loris (3) , Joost Schymkowitz (4) , Frederic Rousseau (4) , Pascale Zimmermann (1, 2)

1 CRCM - Centre de Recherche en Cancérologie de Marseille
2 Department of Human Genetics, University of Leuven, Leuven, Belgium
3 SBB - Structural Biology Brussels
4 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven

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 (PIP 2). The crystal structure reveals a tripartite interaction formed via the second PDZ domain of syntenin. Biophysical and biochemical experiments establish cooperative binding of the tripartite complex and identify residues crucial for membrane PIP 2-specific recognition. Experiments with cells support the importance of the syntenin–PIP 2 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.

Mots clés: Cell signalling; G protein-coupled receptors; Membrane biophysics; Membrane trafficking

Domaines: Sciences du Vivant [q-bio]

Antonio Luis Egea-Jimenez, Rodrigo Gallardo, Abel Garcia-Pino, Ylva Ivarsson, Anna Maria Wawrzyniak, et al.. Frizzled 7 and PIP2 binding by syntenin PDZ2 domain supports Frizzled 7 trafficking and signalling. Nature Communications, 2016, 7, ⟨10.1038/ncomms12101⟩. ⟨hal-01787573⟩