Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors.
Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors.
复制标题
DOI：
10.1073/pnas.2007511118
复制
发表时间：
2021-01-12
影响因子：
11.1
通讯作者：
Popescu GK
中科院分区：
文献类型：
--
作者：
Iacobucci GJ;Wen H;Helou M;Liu B;Zheng W;Popescu GK
NMDA受体是谷氨酸能通道，其激活控制中枢神经系统兴奋性突触的强度。激动剂结合可启动复杂的激活反应，该反应由可逆异构化的逐步序列组成。除了先前确定的这一系列步骤，包括激动剂诱导的配体结合叶的关闭，以及随后配体结合结构域对形成门的跨膜螺旋的机械拉动，我们还发现了一种跨亚单位相互作用，它稳定了开放的受体，减缓了电流衰减的速度。缺乏这种相互作用的自然产生的NMDA受体变体是致病的。NMDA受体是中枢突触生理中具有重要作用的兴奋性通道。它们的活化反应是通过一系列动力学上可区分的可逆步骤进行的，其结构基础目前正在研究中。很可能，最早的步骤包括谷氨酸与甘氨酸结合受体的结合，以及随后配体结合区域的收缩。随后，三个短连接子通过机械拉动跨膜螺旋来转导这一运动以打开门。在这里，我们使用分子和动力学模拟以及双突变循环分析来证明GluN1-I642(在M3螺旋上)和GluN2A-L550(在L1-M1连接子上)之间的直接化学相互作用在受体打开后保持稳定，从而代表了激活反应后期发生的结构变化之一。这种天然的相互作用延长了电流的衰减，它的缺失会导致致病人类变种GluN1-I642L的电荷转移不足。
NMDA receptors are glutamatergic channels whose activation controls the strength of excitatory synapses in the central nervous system. Agonist binding initiates a complex activation reaction that consists of a stepwise sequence of reversible isomerizations. In addition to previously identified steps in this series, which include agonist-induced closure of the ligand-binding lobes and the subsequent mechanical pulling by the ligand-binding domain on the gate-forming transmembrane helix, we identify a cross-subunit interaction that stabilizes open receptors and slows the rate of the current decay. Naturally occurring NMDA receptor variants lacking this interaction are pathogenic. NMDA receptors are excitatory channels with critical functions in the physiology of central synapses. Their activation reaction proceeds as a series of kinetically distinguishable, reversible steps, whose structural bases are currently under investigation. Very likely, the earliest steps include glutamate binding to glycine-bound receptors and subsequent constriction of the ligand-binding domain. Later, three short linkers transduce this movement to open the gate by mechanical pulling on transmembrane helices. Here, we used molecular and kinetic simulations and double-mutant cycle analyses to show that a direct chemical interaction between GluN1-I642 (on M3 helix) and GluN2A-L550 (on L1-M1 linker) stabilizes receptors after they have opened and thus represents one of the structural changes that occur late in the activation reaction. This native interaction extends the current decay, and its absence causes deficits in charge transfer by GluN1-I642L, a pathogenic human variant.
登录
查看更多内容
影响因子：
64.5
作者：
CARTER, PJ;WINTER, G;FERSHT, AR
通讯作者：
FERSHT, AR
影响因子：
5.3
作者：
Kussius, Cassandra L.;Kaur, Navjot;Popescu, Gabriela K.
通讯作者：
Popescu, Gabriela K.
影响因子：
4.8
作者：
Maki, Bruce A.;Aman, Teresa K.;Popescu, Gabriela K.
通讯作者：
Popescu, Gabriela K.
影响因子：
3.6
作者：
Ogden, Kevin K.;Traynelis, Stephen F.
通讯作者：
Traynelis, Stephen F.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G