High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the TrK receptors

Roman Urfer, Pantelis Tsoulfas, Lori O'Connell, Jo Anne Hongo, Wei Zhao, Leonard G. Presta

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Neurotrophic factors are important for survival and maintenance of neurons during developmental and adult stages of the vertebrate nervous system. The neurotrophins mediate their signal into the cell by specific interaction with tyrosine kinase receptors of the Trk family. The extracellular immunoglobulin-like domain of the Trk receptors adjacent to the membrane has previously been shown to be the dominant element for specific neurotrophin binding. Using computer graphics models of the human TrkA and TrkC immunoglobulin-like domains as a guide, the residues involved in binding to their respective neurotrophins were mapped by mutational analysis. TrkC primarily utilizes loop EF, between β-strands E and F, for binding. In contrast, TrkA utilizes the EF loop as well as additional residues, the latter being prime candidates for determining the specificity of TrkA versus TrkC. When selected TrkC and TrkA mutants with reduced binding were expressed on NIH3T3 cells, neurotrophin-induced autophosphorylation was strongly reduced or absent.

Original languageEnglish (US)
Pages (from-to)5829-5840
Number of pages12
JournalJournal of Biological Chemistry
Volume273
Issue number10
DOIs
StatePublished - Mar 6 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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