Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes.
Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes.
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DOI：
10.1016/j.neuron.2016.01.038
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发表时间：
2016-03-16
期刊：
影响因子：
16.2
通讯作者：
Bowie D
中科院分区：
文献类型：
--
作者：
Dawe GB;Musgaard M;Aurousseau MRP;Nayeem N;Green T;Biggin PC;Bowie D
神经递质门控离子通道采用不同的门控模式来微调中枢突触的信号传导。在突触，高和低活性的AMPA受体（AMPAR）观察时，孔形成亚基共组装或无辅助亚基，分别。是否一个共同的结构途径占这些不同的门控模式尚不清楚。在这里，我们确定了两个结构基序，确定AMPAR通道激活的时间过程。AMPAR配体结合域（LBD）顶端的静电相互作用网络对于孔形成亚基的门控是必不可少的，而当辅助亚基存在时，LBD下部D2叶上的保守基序抑制通道活性。因此，通道活性几乎完全消除消除静电网络，但恢复通过辅助蛋白质相互作用在D2叶。总之，我们提出，本地AMPAR复合物的激活是协调不同的结构途径，有利于辅助亚基的关联/解离。两种不同的结构基序控制AMPA受体门控的时间过程蛋白内静电相互作用通过成孔亚基控制门控辅助亚基在不同的位点起作用以延长通道活性蛋白内和蛋白间相互作用通过AMPA受体复合物协调信号传导结合电生理学、分子动力学模拟和X射线晶体学，Dawe et al.确定了两个不同的结构图案，协调门控AMPA受体辅助亚基复合物，突出内和蛋白间的相互作用在快速兴奋性信号的重要性。
Neurotransmitter-gated ion channels adopt different gating modes to fine-tune signaling at central synapses. At glutamatergic synapses, high and low activity of AMPA receptors (AMPARs) is observed when pore-forming subunits coassemble with or without auxiliary subunits, respectively. Whether a common structural pathway accounts for these different gating modes is unclear. Here, we identify two structural motifs that determine the time course of AMPAR channel activation. A network of electrostatic interactions at the apex of the AMPAR ligand-binding domain (LBD) is essential for gating by pore-forming subunits, whereas a conserved motif on the lower, D2 lobe of the LBD prolongs channel activity when auxiliary subunits are present. Accordingly, channel activity is almost entirely abolished by elimination of the electrostatic network but restored via auxiliary protein interactions at the D2 lobe. In summary, we propose that activation of native AMPAR complexes is coordinated by distinct structural pathways, favored by the association/dissociation of auxiliary subunits. Two distinct structural motifs control the time course of AMPA receptor gating Intraprotein electrostatic interactions govern gating by pore-forming subunits Auxiliary subunits act at a distinct site to prolong channel activity Intra- and interprotein interactions coordinate signaling by AMPA receptor complexes Combining electrophysiology, molecular dynamics simulations, and X-ray crystallography, Dawe et al. identify two distinct structural motifs that coordinate the gating of AMPA receptor-auxiliary subunit complexes, highlighting the importance of intra- and interprotein interactions in fast excitatory signaling.