Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors

Neuron. 2007 Jan 4;53(1):25-38. doi: 10.1016/j.neuron.2006.09.034.


Nerve growth factor engages two structurally distinct transmembrane receptors, TrkA and p75, which have been proposed to create a "high-affinity" NGF binding site through formation of a ternary TrkA/NGF/p75 complex. To define a structural basis for the high-affinity site, we have determined the three-dimensional structure of a complete extracellular domain of TrkA complexed with NGF. The complex reveals a crab-shaped homodimeric TrkA structure, but a mechanism for p75 coordination is not obvious. We investigated the heterodimerization of membrane-bound TrkA and p75, on intact mammalian cells, using a beta-gal protein-protein interaction system. We find that NGF dimerizes TrkA and that p75 exists on the cell surface as a preformed oligomer that is not dissociated by NGF. We find no evidence for a direct TrkA/p75 interaction. We propose that TrkA and p75 likely communicate through convergence of downstream signaling pathways and/or shared adaptor molecules, rather than through direct extracellular interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / physiology
  • Cell Line
  • Cell Membrane / metabolism*
  • Cell Membrane / ultrastructure
  • Dimerization
  • Extracellular Space / metabolism
  • Humans
  • Ligands
  • Macromolecular Substances / chemistry
  • Macromolecular Substances / metabolism
  • Mice
  • Models, Molecular
  • Nerve Growth Factor / chemistry*
  • Nerve Growth Factor / metabolism
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Protein Structure, Tertiary / physiology
  • Receptor, Nerve Growth Factor / chemistry*
  • Receptor, Nerve Growth Factor / metabolism
  • Receptor, trkA / chemistry*
  • Receptor, trkA / metabolism
  • Signal Transduction / physiology


  • Ligands
  • Macromolecular Substances
  • Receptor, Nerve Growth Factor
  • Nerve Growth Factor
  • Receptor, trkA

Associated data

  • PDB/2IFG