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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.

Original publication

DOI

10.1038/emboj.2011.346

Type

Journal article

Journal

EMBO J

Publication Date

23/09/2011

Volume

30

Pages

4479 - 4488

Keywords

GPI-Linked Proteins, HEK293 Cells, Humans, Ligands, Membrane Glycoproteins, Models, Biological, Models, Molecular, Nerve Tissue Proteins, Netrins, Protein Binding, Protein Conformation, Receptors, Cell Surface, Synapses, Tissue Distribution, Transfection