title: Frizzled 7 and PIP2 binding by syntenin PDZ2 domain supports Frizzled 7 trafficking and signalling.
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.
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France.|Department of Human Genetics, KU Leuven, ON1 Herestraat 49 Box 602, B-3000 Leuven, Belgium.
authors.forename: Antonio Luis
authors.initials: AL
authors.lastname: Egea-Jimenez
authors.affiliation: Department of Human Genetics, KU Leuven, ON1 Herestraat 49 Box 602, B-3000 Leuven, Belgium.|VIB Switch Laboratory, Department of Molecular Cellular and Molecular Medicine, VIB-KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Gallardo
authors.affiliation: Structural Biology Brussels, Deptartment of Biotechnology (DBIT), Vrije Universiteit Brussel and Molecular Recognition Unit, Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussel, Belgium.
authors.forename: Abel
authors.initials: A
authors.lastname: Garcia-Pino
authors.affiliation: Department of Human Genetics, KU Leuven, ON1 Herestraat 49 Box 602, B-3000 Leuven, Belgium.
authors.forename: Ylva
authors.identifier: 0000-0002-7081-3846
authors.initials: Y
authors.lastname: Ivarsson
authors.affiliation: Department of Human Genetics, KU Leuven, ON1 Herestraat 49 Box 602, B-3000 Leuven, Belgium.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Wawrzyniak
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France.|Department of Human Genetics, KU Leuven, ON1 Herestraat 49 Box 602, B-3000 Leuven, Belgium.
authors.forename: Rudra
authors.initials: R
authors.lastname: Kashyap
authors.affiliation: Structural Biology Brussels, Deptartment of Biotechnology (DBIT), Vrije Universiteit Brussel and Molecular Recognition Unit, Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussel, Belgium.
authors.forename: Remy
authors.initials: R
authors.lastname: Loris
authors.affiliation: VIB Switch Laboratory, Department of Molecular Cellular and Molecular Medicine, VIB-KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Joost
authors.identifier: 0000-0003-2020-0168
authors.initials: J
authors.lastname: Schymkowitz
authors.affiliation: VIB Switch Laboratory, Department of Molecular Cellular and Molecular Medicine, VIB-KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France.|Department of Human Genetics, KU Leuven, ON1 Herestraat 49 Box 602, B-3000 Leuven, Belgium.
authors.forename: Pascale
authors.identifier: 0000-0001-8768-1790
authors.initials: P
authors.lastname: Zimmermann
mesh_terms: D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D051157:Frizzled Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D054731:PDZ Domains; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053676:Syntenins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C115810:FZD7 protein, human; D051157:Frizzled Receptors; D019269:Phosphatidylinositol 4,5-Diphosphate; D011994:Recombinant Proteins; D053676:Syntenins