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

• Published in: Neuron (Cambridge, Mass.) Vol. 62; no. 1; pp. 72 - 83
• Main Authors: Vilar, Marcal, Charalampopoulos, Ioannis, Kenchappa, Rajappa S, Simi, Anastasia, Karaca, Esra, Reversi, Alessandra, Choi, Soyoung, Bothwell, Mark, Mingarro, Ismael, Friedman, Wilma J, Schiavo, Giampietro, Bastiaens, Philippe IH, Verveer, Peter J, Carter, Bruce D, Ibanez, Carlos F
• Format: Journal Article
• Language: English
• Published: 01.04.2009
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2009.02.020Article

Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75 super(NTR)), but the mechanism of receptor activation has remained elusive. Here, we show that p75 super(NTR) forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys super(257) in its transmembrane domain. Mutation of Cys super(257) abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75 super(NTR)/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75 super(NTR). FRET experiments revealed a close association of p75 super(NTR) intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys super(257) did not alter the oligomeric state of p75 super(NTR), the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75 super(NTR) by a mechanism involving rearrangement of disulphide-linked receptor subunits.