Structural basis of NF-κB signaling by the p75 neurotrophin receptor interaction with adaptor protein TRADD through their respective death domains.
Structural basis of NF-κB signaling by the p75 neurotrophin receptor interaction with adaptor protein TRADD through their respective death domains.
复制标题
DOI：
10.1016/j.jbc.2021.100916
复制
发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Lin Z
中科院分区：
文献类型：
--
作者：
Zhang N;Kisiswa L;Ramanujan A;Li Z;Sim EW;Tian X;Yuan W;Ibáñez CF;Lin Z
p75神经营养因子受体（p75NTR）是神经元死亡和组织重塑的重要介质，与多种神经退行性疾病和癌症有关。p75NTR的死亡结构域（DD）是一个细胞内信号中枢，并已被证明与多种接头蛋白相互作用。在乳腺癌细胞中，接头蛋白TRADD与p75NTR的结合依赖于神经生长因子并促进细胞存活。然而，TRADD募集在神经元p75NTR信号传导中的结构机制和功能意义尚不清楚。本文报道了p75NTR-DD和TRADD-DD复合物的核磁共振结构，揭示了p75NTR-DD主要通过静电相互作用特异性识别TRADD-DD的机制。此外，我们发现p75NTR和TRADD表达在出生后早期发育中的小脑颗粒神经元（CGNs）中存在时空重叠，并发现TRADD和p75NTR相互作用在调节典型NF-κB信号传导和CGNs细胞存活中的生理相关性。我们的研究结果为理解TRADD如何通过DD相互作用募集到p75NTR提供了一个新的结构框架，该平台可以通过p75NTR的细胞外结构域有效地受到各种神经营养因子的调节，从而在发育中的神经元中传播下游信号。
The p75 neurotrophin receptor (p75NTR) is a critical mediator of neuronal death and tissue remodeling and has been implicated in various neurodegenerative diseases and cancers. The death domain (DD) of p75NTR is an intracellular signaling hub and has been shown to interact with diverse adaptor proteins. In breast cancer cells, binding of the adaptor protein TRADD to p75NTR depends on nerve growth factor and promotes cell survival. However, the structural mechanism and functional significance of TRADD recruitment in neuronal p75NTR signaling remain poorly understood. Here we report an NMR structure of the p75NTR-DD and TRADD-DD complex and reveal the mechanism of specific recognition of the TRADD-DD by the p75NTR-DD mainly through electrostatic interactions. Furthermore, we identified spatiotemporal overlap of p75NTR and TRADD expression in developing cerebellar granule neurons (CGNs) at early postnatal stages and discover the physiological relevance of the interaction between TRADD and p75NTR 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 p75NTR through DD interactions creates a membrane-proximal platform, which can be efficiently regulated by various neurotrophic factors through extracellular domains of p75NTR, to propagate downstream signaling in developing neurons.
登录
查看更多内容
影响因子：
3.4
作者：
Li, Minfen;Liu, Jingxian;Song, Jianxing
通讯作者：
Song, Jianxing
影响因子：
4.3
作者：
Pobezinskaya, Yelena L.;Liu, Zhenggang
通讯作者：
Liu, Zhenggang
影响因子：
64.5
作者：
JOHNSON, D;LANAHAN, A;CHAO, M
通讯作者：
CHAO, M
影响因子：
64.5
作者：
Park, YC;Ye, H;Wu, H
通讯作者：
Wu, H
影响因子：
3
作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE