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

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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
    KU Leuven)

  • Rodrigo Gallardo

    (KU Leuven
    VIB Switch Laboratory)

  • Abel Garcia-Pino

    (Structural Biology Brussels, Deptartment of Biotechnology (DBIT), Vrije Universiteit Brussel and Molecular Recognition Unit, Structural Biology Research Center
    Present address: Biologie Structurale et Biophysique, Université Libre de Bruxelles, CP300, rue des Professeurs Jeener et Brachet 12, B-6041 Gosselies, Belgium)

  • Ylva Ivarsson

    (KU Leuven
    Present address: Department of Chemistry—BMC, Uppsala University, Husargatan 3, 751 23 Uppsala, Sweden)

  • 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
    KU Leuven)

  • 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
    KU Leuven)

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.

Suggested Citation

  • Antonio Luis Egea-Jimenez & Rodrigo Gallardo & Abel Garcia-Pino & Ylva Ivarsson & Anna Maria Wawrzyniak & Rudra Kashyap & Remy Loris & Joost Schymkowitz & Frederic Rousseau & Pascale Zimmermann, 2016. "Frizzled 7 and PIP2 binding by syntenin PDZ2 domain supports Frizzled 7 trafficking and signalling," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12101
    DOI: 10.1038/ncomms12101
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