A Conformational Intermediate in Glutamate Receptor Activation
A Conformational Intermediate in Glutamate Receptor Activation
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DOI：
10.1016/j.neuron.2013.06.003
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发表时间：
2013-08-07
期刊：
影响因子：
16.2
通讯作者：
Roux, Benoit
中科院分区：
文献类型：
--
作者：
Lau, Albert Y.;Salazar, Hector;Roux, Benoit
嗜电性谷氨酸受体（iGluRs）将神经递质释放的化学信号传导到脑兴奋性突触的膜去极化。这些配体门控受体的跨膜离子通道的打开是由谷氨酸分子与配体结合域（lbd）结合诱导的构象转变驱动的。在这里，我们描述了GluA2 LBD四聚体的晶体结构，其结构涉及LBD基团相对于全长受体的晶体结构的类似30度旋转。结构是由一个工程二硫交联稳定。对包含这种交联或工程金属桥的全长受体的生化和电生理学研究表明，这种LBD结构对应于受体激活的中间状态。因此，GluA2的激活涉及lbd内（裂缝关闭）和lbd间二聚体构象转变的组合。总的来说，这些结果提供了iGluR中间态的全面结构表征。
Ionotropic glutamate receptors (iGluRs) transduce the chemical signal of neurotransmitter release into membrane depolarization at excitatory synapses in the brain. The opening of the transmembrane ion channel of these ligand-gated receptors is driven by conformational transitions that are induced by the association of glutamate molecules to the ligand-binding domains (LBDs). Here, we describe the crystal structure of a GluA2 LBD tetramer in a configuration that involves an similar to 30 degrees rotation of the LBD dinners relative to the crystal structure of the full-length receptor. The configuration is stabilized by an engineered disulfide crosslink. Biochemical and electrophysiological studies on full-length receptors incorporating either this crosslink or an engineered metal bridge show that this LBD configuration corresponds to an intermediate state of receptor activation. GluA2 activation therefore involves a combination of both intra-LBD (cleft closure) and inter-LBD dimer conformational transitions. Overall, these results provide a comprehensive structural characterization of an iGluR intermediate state.