title: Structural basis for cell surface patterning through NetrinG-NGL interactions.
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.
authors.affiliation: Division of Structural Biology, CR-UK Receptor Structure Research Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Seiradake
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Coles
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Perestenko
authors.forename: Karl
authors.initials: K
authors.lastname: Harlos
authors.forename: Robert Andrew Jeffrey
authors.initials: RA
authors.lastname: McIlhinney
authors.forename: Alexandru Radu
authors.initials: AR
authors.lastname: Aricescu
authors.forename: Edith Yvonne
authors.initials: EY
authors.lastname: Jones
mesh_terms: D058851:GPI-Linked Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000075385:Netrins; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D058851:GPI-Linked Proteins; C568998:LRRC4B protein, human; C480698:LRRC4C protein, human; D008024:Ligands; D008562:Membrane Glycoproteins; C463082:NTNG1 protein, human; C463083:NTNG2 protein, human; D009419:Nerve Tissue Proteins; D000075385:Netrins; D011956:Receptors, Cell Surface