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First published online 25 August 2009
doi: 10.1242/jcs.055061

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Ligand-independent signaling by disulfide-crosslinked dimers of the p75 neurotrophin receptor

Marçal Vilar^1,*, Ioannis Charalampopoulos^1,, Rajappa S. Kenchappa², Alessandra Reversi³, Joanna M. Klos-Applequist⁴, Esra Karaca¹, Anastasia Simi¹, Carlos Spuch^1,*, Soyoung Choi⁵, Wilma J. Friedman⁵, Johan Ericson⁴, Giampietro Schiavo³, Bruce D. Carter² and Carlos F. Ibáñez^1,

¹ Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden
² Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
³ Molecular NeuroPathobiology Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
⁴ Department of Cell and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden
⁵ Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA

Author for correspondence (carlos.ibanez{at}ki.se)

Accepted 15 July 2009

Dimerization is recognized as a crucial step in the activation of many plasma membrane receptors. However, a growing number of receptors pre-exist as dimers in the absence of ligand, indicating that, although necessary, dimerization is not always sufficient for signaling. The p75 neurotrophin receptor (p75^NTR) forms disulfide-linked dimers at the cell surface independently of ligand binding through Cys257 in its transmembrane domain. Here, we show that crosslinking of p75^NTR dimers by cysteine-scanning mutagenesis results in constitutive, ligand-independent activity in several pathways that are normally engaged upon neurotrophin stimulation of native receptors. The activity profiles of different disulfide-crosslinked p75^NTR mutants were similar but not identical, suggesting that different configurations of p75^NTR dimers might be endowed with different functions. Interestingly, crosslinked p75^NTR mutants did not mimic the effects of the myelin inhibitors Nogo or MAG, suggesting the existence of ligand-specific activation mechanisms. Together, these results support a conformational model of p75^NTR activation by neurotrophins, and reveal a genetic approach to generate gain-of-function receptor variants with distinct functional profiles.

Key words: Intracellular signaling, Nerve growth factor, Receptor activation, Receptor dimerization

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