Structural basis for cell surface patterning through NetrinG-NGL interactions

EMBO J. 2011 Sep 23;30(21):4479-88. doi: 10.1038/emboj.2011.346.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • GPI-Linked Proteins / chemistry
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Ligands
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Models, Biological
  • Models, Molecular
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Netrins
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Protein Conformation
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Synapses / metabolism
  • Tissue Distribution
  • Transfection

Substances

  • GPI-Linked Proteins
  • LRRC4B protein, human
  • LRRC4C protein, human
  • Ligands
  • Membrane Glycoproteins
  • NTNG1 protein, human
  • NTNG2 protein, human
  • Nerve Tissue Proteins
  • Netrins
  • Receptors, Cell Surface