Structural basis of death domain signaling in the p75 neurotrophin receptor
Zhi Lin,
Jason Y Tann,
Eddy TH Goh,
Claire Kelly,
Kim Buay Lim,
Jian Fang Gao,
Carlos F Ibanez
Affiliations
Zhi Lin
Department of Physiology, National University of Singapore, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore
Jason Y Tann
Department of Physiology, National University of Singapore, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore
Eddy TH Goh
Department of Physiology, National University of Singapore, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore
Claire Kelly
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Kim Buay Lim
Department of Physiology, National University of Singapore, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore
Jian Fang Gao
Department of Physiology, National University of Singapore, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore
Carlos F Ibanez
Department of Physiology, National University of Singapore, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore; Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Death domains (DDs) mediate assembly of oligomeric complexes for activation of downstream signaling pathways through incompletely understood mechanisms. Here we report structures of complexes formed by the DD of p75 neurotrophin receptor (p75NTR) with RhoGDI, for activation of the RhoA pathway, with caspase recruitment domain (CARD) of RIP2 kinase, for activation of the NF-kB pathway, and with itself, revealing how DD dimerization controls access of intracellular effectors to the receptor. RIP2 CARD and RhoGDI bind to p75NTR DD at partially overlapping epitopes with over 100-fold difference in affinity, revealing the mechanism by which RIP2 recruitment displaces RhoGDI upon ligand binding. The p75NTR DD forms non-covalent, low-affinity symmetric dimers in solution. The dimer interface overlaps with RIP2 CARD but not RhoGDI binding sites, supporting a model of receptor activation triggered by separation of DDs. These structures reveal how competitive protein-protein interactions orchestrate the hierarchical activation of downstream pathways in non-catalytic receptors.
