Structural and functional elucidation of NF-κB signaling by the p75 neurotrophin receptor through recruitment of TRADD

p75 neurotrophin receptor (p75 NTR ) is a critical mediator of neuronal death and tissue remodeling and has been implicated in various neurodegenerative diseases. The death domain (DD) of p75 NTR is an intracellular signaling hub and has been shown to interact with diverse adaptor proteins. However, the structural mechanism and physiological relevance of the adaptor protein TRADD in neuronal p75 NTR signaling remain poorly understood. Here we report an NMR structure of the complex between p75 NTR -DD and TRADD-DD and elucidate the structural basis of specific DD recognition in the p75 NTR /TRADD signaling pathway. Furthermore, we identify spatiotemporal overlap of p75 NTR and TRADD expression in developing cerebellar granule neurons (CGNs) at early postnatal stages and reveal the functional role of TRADD recruitment to p75 NTR in the regulation of canonical NF-κB signaling and cell survival in CGNs. Our results provide a new structural framework for understanding how the recruitment of TRADD to p75 NTR through DD interactions creates a membrane-proximal platform to propagate downstream signaling in developing neurons.