Activation of the p75 Neurotrophin Receptor through Conformational Rearrangement of Disulphide-Linked Receptor Dimers

Marçal Vilar, Ioannis Charalampopoulos, Rajappa S. Kenchappa, Anastasia Simi, Esra Karaca, Alessandra Reversi, Soyoung Choi, Mark Bothwell, Ismael Mingarro, Wilma J. Friedman, Giampietro Schiavo, Philippe I.H. Bastiaens, Peter J. Verveer, Bruce D. Carter, Carlos F. Ibáñez

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75NTR), but the mechanism of receptor activation has remained elusive. Here, we show that p75NTR forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys257 in its transmembrane domain. Mutation of Cys257 abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75NTR/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75NTR. FRET experiments revealed a close association of p75NTR intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys257 did not alter the oligomeric state of p75NTR, the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75NTR by a mechanism involving rearrangement of disulphide-linked receptor subunits.

Original languageEnglish (US)
Pages (from-to)72-83
Number of pages12
JournalNeuron
Volume62
Issue number1
DOIs
StatePublished - Apr 16 2009

Keywords

  • MOLNEURO
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Neuroscience(all)

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