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

• 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 (p75NTR) forms disulfide-linked dimers at the cell surface independently of ligand binding through Cys257 in its transmembrane domain. Here, we show that crosslinking of p75NTR 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 p75NTR mutants were similar but not identical, suggesting that different configurations of p75NTR dimers might be endowed with different functions. Interestingly, crosslinked p75NTR 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 p75NTR activation by neurotrophins, and reveal a genetic approach to generate gain-of-function receptor variants with distinct functional profiles.

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