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Structural basis for cell surface patterning through NetrinG-NGL interactions.

DOI: 10.1038/emboj.2011.346 DOI Help
PMID: 21946559 PMID Help

Authors: Elena Seiradake (Wellcome Trust Centre for Human Genetics, University of Oxford, U.K.) , Charlotte H Coles (Wellcome Trust Centre for Human Genetics, University of Oxford, U.K.) , Pavel V Perestenko (MRC Anatomical Neuropharmacology Unit, University of Oxford, U.K.) , Karl Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford, U.K.) , Robert Andrew Jeffrey Mcilhinney (MRC Anatomical Neuropharmacology Unit, University of Oxford, U.K.) , E Yvonne Jones (Wellcome Trust Centre for Human Genetics, University of Oxford, U.K.) , Alexandru Radu Aricescu (Wellcome Trust Centre for Human Genetics, University of Oxford, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal , VOL 30 (21) , PAGES 4479 - 4488

State: Published (Approved)
Published: December 2011

Open Access Open Access

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.

Journal Keywords: HEK293; Humans; Ligands; Membrane; Models; Biological; Models; Molecular; Nerve; Protein; Receptors; Cell; Synapses; Tissue; Transfection

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)