Structure and functional relevance of the Slit2 homodimerization domain |
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Authors: | Elena Seiradake Anne C von Philipsborn Maud Henry Martin Fritz Hugues Lortat-Jacob Marc Jamin Wieger Hemrika Martin Bastmeyer Stephen Cusack and Andrew A McCarthy |
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Institution: | 1. Zoologisches Institut, Universitaet Karlsruhe (TH), Zell‐ und Neurobiologie, Haid‐und‐Neu‐Strasse 9, 76131 Karlsruhe, Germany;2. European Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, 38042 Grenoble Cedex 9, France;3. Unit of Virus Host‐Cell Interactions, UJF‐EMBL‐CNRS, UMR 5233, 6 rue Jules Horowitz, 38042 Grenoble Cedex 9, France;4. IBS, Institut de Biologie Structurale, UMR 5075 CNRS‐CEA‐UJF, 41 rue Horowitz, 38027 Grenoble Cedex 01, France;5. U‐Protein Express B.V. Padualaan 8, 3584 CH Utrecht, The Netherlands |
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Abstract: | Slit proteins are secreted ligands that interact with the Roundabout (Robo) receptors to provide important guidance cues in neuronal and vascular development. Slit–Robo signalling is mediated by an interaction between the second Slit domain and the first Robo domain, as well as being dependent on heparan sulphate. In an effort to understand the role of the other Slit domains in signalling, we determined the crystal structure of the fourth Slit2 domain (D4) and examined the effects of various Slit2 constructs on chick retinal ganglion cell axons. Slit2 D4 forms a homodimer using the conserved residues on its concave face, and can also bind to heparan sulphate. We observed that Slit2 D4 frequently results in growth cones with collapsed lamellipodia and that this effect can be inhibited by exogenously added heparan sulphate. Our results show that Slit2 D4–heparan sulphate binding contributes to a Slit–Robo signalling mechanism more intricate than previously thought. |
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Keywords: | neurons guidance cues signalling |
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