Structural basis for cell surface patterning through NetrinG-NGL interactions |
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Authors: | Seiradake Elena Coles Charlotte H Perestenko Pavel V Harlos Karl McIlhinney Robert Andrew Jeffrey Aricescu Alexandru Radu Jones Edith Yvonne |
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Affiliation: | Division of Structural Biology, CR-UK Receptor Structure Research Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. |
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Abstract: | Brain wiring depends on cells making highly localized and selective connections through surface protein-protein interactions, including those between NetrinGs and NetrinG ligands (NGLs). The NetrinGs are members of the structurally uncharacterized netrin family. We present a comprehensive crystallographic analysis comprising NetrinG1-NGL1 and NetrinG2-NGL2 complexes, unliganded NetrinG2 and NGL3. Cognate NetrinG-NGL interactions depend on three specificity-conferring NetrinG loops, clasped tightly by matching NGL surfaces. We engineered these NGL surfaces to implant custom-made affinities for NetrinG1 and NetrinG2. In a cellular patterning assay, we demonstrate that NetrinG-binding selectivity can direct the sorting of a mixed population of NGLs into discrete cell surface subdomains. These results provide a molecular model for selectivity-based patterning in a neuronal recognition system, dysregulation of which is associated with severe neuropsychological disorders. |
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Keywords: | brain patterning crystal structure protein engineering schizophrenia synaptic adhesion |
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