Evolution of Eukaryotic Ion Channels: Principles Underlying the Conversion of Ca2+-Selective to Na+-Selective Channels

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• 作者：Todor Dudev ; Carmay Lim
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：March 5, 2014
• 年：2014
• 卷：136
• 期：9
• 页码：3553-3559
• 全文大小：378K
• 年卷期：v.136,no.9(March 5, 2014)
• ISSN：1520-5126

文摘

Ion selectivity of four-domain voltage-gated Ca²⁺ and Na⁺ channels, which is controlled by the selectivity filter (the narrowest region of an open pore), is crucial for electrical signaling. Over billions of years of evolution, mutation of the Glu from domain II/III in the EEEE/DEEA selectivity filters of Ca²⁺-selective channels to Lys made these channels Na⁺-selective. Why Lys is sufficient for Na⁺ selectivity and why the DKEA selectivity filter is less Na⁺-selective than the DEKA one are intriguing, fundamental questions. By computing the free energy for replacing Ca²⁺ inside model selectivity filters with Na⁺, we find that the nonmetal-ligating Lys in the DKEA/DEKA selectivity filter attenuates metal鈥損rotein interactions to such an extent that solvation effects become dominant, favoring Na⁺. It constricts and rigidifies the DEKA pore to bind Na⁺ optimally, highlighting the importance of lysine鈥檚 nonobvious structural role, in addition to its electrostatic role, in the selectivity of Na⁺ over Ca²⁺.