A Multipoint Hydrogen-Bond Network Underlying KcsA C-Type Inactivation
A Multipoint Hydrogen-Bond Network Underlying KcsA C-Type Inactivation
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DOI：
10.1016/j.bpj.2011.01.073
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发表时间：
2011-05-18
影响因子：
3.4
通讯作者：
Perozo, Eduardo
中科院分区：
文献类型：
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作者：
Cordero-Morales, Julio F.;Jogini, Vishwanath;Perozo, Eduardo
在原核钾通道中，KCSA在内束门的激活门控之后是选择性过滤器的C型失活。进入C型失活状态与过滤器后面残基Glu-71和Asp-80之间的氢键相互作用的强度直接相关，并由内束门的重排变构触发。在这里，我们证明了残基Trp-67和Asp-80之间的氢键配对，在大多数K+通道中保守，构成了另一个关键的相互作用，决定了KCsA C型失活的速度和程度。Shaker(Trp-434-Asp-447)和Kv1.2(Trp-366-Asp-379)中的等效相互作用的破坏也导致了失活过程的调制，表明这些残基在Kv通道的失活门控中也起着类似的作用。结果表明，在KCSA中，C型失活门控是由Trp-67-G1u71-Asp-80三联体形成的多点氢键网络控制的。这个三联体在选择性过滤器的动力学和构象稳定性中起着关键作用，并可能在K+通道家族的其他成员中作为选择性过滤器门控的通用调节器。
In the prokaryotic potassium channel KcsA activation gating at the inner bundle gate is followed by C-type inactivation at the selectivity filter. Entry into the C-type inactivated state has been directly linked to the strength of the H-bond interaction between residues Glu-71 and Asp-80 behind the filter, and is allosterically triggered by the rearrangement of the inner bundle gate. Here, we show that H-bond pairing between residues Trp-67 and Asp-80, conserved in most K+ channels, constitutes another critical interaction that determines the rate and extent of KcsA C-type inactivation. Disruption of the equivalent interaction in Shaker (Trp-434-Asp-447) and Kv1.2 (Trp-366-Asp-379) leads also to modulation of the inactivation process, suggesting that these residues also play an analogous role in the inactivation gating of Kv channels. The present results show that in KcsA C-type inactivation gating is governed by a multipoint hydrogen-bond network formed by the triad Trp-67-G1u71-Asp-80. This triad exerts a critical role in the dynamics and conformational stability of the selectivity filter and might serve as a general modulator of selectivity filter gating in other members of the K+ channel family.