Structural mechanism for signal transduction in RXR nuclear receptor heterodimers.
Structural mechanism for signal transduction in RXR nuclear receptor heterodimers.
复制标题
RXR核受体异二聚体中信号转导的结构机制。
DOI：
10.1038/ncomms9013
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发表时间：
2015-08-20
影响因子：
16.6
通讯作者：
Nettles KW
中科院分区：
文献类型：
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作者：
Kojetin DJ;Matta-Camacho E;Hughes TS;Srinivasan S;Nwachukwu JC;Cavett V;Nowak J;Chalmers MJ;Marciano DP;Kamenecka TM;Shulman AI;Rance M;Griffin PR;Bruning JB;Nettles KW
核受体（NR）的一个子集作为与类维生素A X受体（RXR）的专性异二聚体发挥作用，允许通过未知的结构机制将配体依赖性信号整合到二聚体界面。使用核磁共振（NMR）光谱，X射线晶体学和氢/氘交换（HDX）质谱，在这里，我们显示了一种变构机制，通过该机制，RXR与允许的二聚体伴侣，过氧化物酶体增殖物激活受体（PPAR）-γ合作，而通常不响应非允许的二聚体伴侣，甲状腺激素（TR）受体。介导这种变构机制的氨基酸残基包括通过统计偶联分析（SCA）发现的进化上保守的网络。该SCA网络充当信号变阻器以整合二聚体伴侣、配体和辅调节剂结合位点之间的信号，从而影响RXR异源二聚体中的信号传递。这些发现定义了指导NR如何将两个配体依赖性信号通路整合到RXR异源二聚体特异性反应中的规则。 一些核受体与类维生素A X受体二聚化以允许配体依赖性信号传导。在这里，Kojetin等人使用结构和生物物理技术来识别引导这些复杂信号网络的结构变化。
A subset of nuclear receptors (NRs) function as obligate heterodimers with retinoid X receptor (RXR), allowing integration of ligand-dependent signals across the dimer interface via an unknown structural mechanism. Using nuclear magnetic resonance (NMR) spectroscopy, x-ray crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry, here we show an allosteric mechanism through which RXR co-operates with a permissive dimer partner, peroxisome proliferator-activated receptor (PPAR)-γ, while rendered generally unresponsive by a non-permissive dimer partner, thyroid hormone (TR) receptor. Amino acid residues that mediate this allosteric mechanism comprise an evolutionarily conserved network discovered by statistical coupling analysis (SCA). This SCA network acts as a signalling rheostat to integrate signals between dimer partners, ligands and coregulator-binding sites, thereby affecting signal transmission in RXR heterodimers. These findings define rules guiding how NRs integrate two ligand-dependent signalling pathways into RXR heterodimer-specific responses. Some nuclear receptors dimerize with retinoid X receptor to allow ligand-dependent signalling. Here, Kojetin et al. use structural and biophysical techniques to identify structural changes that guide these complex signalling networks.