Structure and desensitization of AMPA receptor complexes with type II TARP γ5 and GSG1L.
Structure and desensitization of AMPA receptor complexes with type II TARP γ5 and GSG1L.
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AMPA受体与II型TARP γ5和GSG1L复合物的结构和脱敏作用。
DOI：
10.1016/j.molcel.2021.09.030
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发表时间：
2021-12-02
期刊：
影响因子：
16
通讯作者：
Sobolevsky AI
中科院分区：
文献类型：
--
作者：
Klykov O;Gangwar SP;Yelshanskaya MV;Yen L;Sobolevsky AI
AMPA受体（AMPAR）介导大多数兴奋性神经传递。它们的表面表达、运输、门控和药理学由辅助亚基调节。在两种类型的TARP辅助亚基中，I型TARP承担激活作用，而II型TARP起抑制作用。我们展示了GluA2 AMPAR与II型TARP γ 5复合的冷冻电镜结构，它降低了稳态电流，增加了单通道电导，并减缓了脱敏的恢复。AMPAR功能的调节依赖于其配体结合结构域（LBD）与γ 5头部结构域的相互作用。GluA2-γ 5复合物显示每个AMPAR四聚体两个TARP的最大化学计量，不同于I型TARP，但使人联想到辅助亚基GSG1L。GluA2-GSG1L和GluA2-γ 5复合物的脱敏都伴随着LBD二聚体界面的破裂，而GluA2-γ 5而不是GluA2-GSG1L LBD二聚体保持2倍对称。AMPAR与辅助亚基复合物的不同结构和脱敏机制赋予了AMPAR广泛的功能。Klykov等人解决了AMPA受体与辅助亚基II型TARP γ 5和GSG1L复合物在封闭和脱敏状态下的结构，每个受体四聚体具有两个辅助亚基的化学计量。GluA2-γ 5和GluA2-GSG1L的失敏伴随着LBD二聚体界面的断裂，但遵循不同的结构机制。
AMPA receptors (AMPARs) mediate the majority of excitatory neurotransmission. Their surface expression, trafficking, gating, and pharmacology are regulated by auxiliary subunits. Of the two types of TARP auxiliary subunits, type I TARPs assume activating roles, while type II TARPs serve suppressive functions. We present cryo-EM structures of GluA2 AMPAR in complex with type II TARP γ5, which reduces steady-state currents, increases single-channel conductance, and slows recovery from desensitization. Regulation of AMPAR function depends on its ligand-binding domain (LBD) interaction with the γ5 head domain. GluA2-γ5 complex shows maximum stoichiometry of two TARPs per AMPAR tetramer, being different from type I TARPs but reminiscent of the auxiliary subunit GSG1L. Desensitization of both GluA2-GSG1L and GluA2-γ5 complexes is accompanied by rupture of LBD dimer interface, while GluA2-γ5 but not GluA2-GSG1L LBD dimers remain 2-fold symmetric. Different structural architectures and desensitization mechanisms of complexes with auxiliary subunits endow AMPARs with broad functional capabilities. Klykov et al. solve structures of AMPA receptor in complex with auxiliary subunits type II TARP γ5 and GSG1L in closed and desensitized states, with stoichiometry of two auxiliary subunits per receptor tetramer. GluA2-γ5 and GluA2-GSG1L desensitization is accompanied by rupture of LBD dimer interface but follows different structural mechanisms.
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影响因子：
48
作者：
Kucukelbir, Alp;Sigworth, Fred J.;Tagare, Hemant D.
通讯作者：
Tagare, Hemant D.
影响因子：
16.2
作者：
Dawe GB;Musgaard M;Aurousseau MRP;Nayeem N;Green T;Biggin PC;Bowie D
通讯作者：
Bowie D
DOI：
10.1523/jneurosci.5613-09.2010
发表时间：
2010-03-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Prieto ML;Wollmuth LP
通讯作者：
Wollmuth LP
影响因子：
56.9
作者：
Nakagawa, Terunaga
通讯作者：
Nakagawa, Terunaga
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K