Structural basis of death domain signaling in the p75 neurotrophin receptor

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Abstract

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 (p75^NTR) 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 p75^NTR 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 p75^NTR 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.

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Zhi Lin

Department of Physiology, National University of Singapore, Singapre, Singapore

Competing interests
The authors declare that no competing interests exist.
Jason Y Tann

Department of Physiology, National University of Singapore, Singapore, Singapore

Competing interests
The authors declare that no competing interests exist.
Eddy TH Goh

Department of Physiology, National University of Singapore, Singapre, Singapore

Competing interests
The authors declare that no competing interests exist.
Claire Kelly

Department of Neuroscience, Karolinska Institute, Stockholm, Sweden

Competing interests
The authors declare that no competing interests exist.
Kim Buay Lim

Department of Physiology, National University of Singapore, Singapore, Singapore

Competing interests
The authors declare that no competing interests exist.
Jian Fang Gao

Department of Physiology, National University of Singapore, Singapore, Singapore

Competing interests
The authors declare that no competing interests exist.
Carlos F Ibanez

Department of Physiology, National University of Singapore, Singapore, Singapore

For correspondence
phscfi@nus.edu.sg

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: Work on Rip2 knock-out mice has been approved by the ethical council of Sweden, ethical protocol number N242/13.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.