Nature2014-06-27 2:07 PM

钙通道的超级选择性 Structural basis for Ca2+ selectivity of a voltage-gated calcium channel

论文摘要 

“电压门控的钙”(CaV)通道具有显著选择性,可帮助Ca2+从细胞外介质(在其中Na+浓度比Ca2+浓度高70倍)中输入。CaV通道是怎样解决这一基本生物物理问题的仍不清楚。这篇研究论文发表了全长度四聚体细菌NaV通道的几个X-射线晶体结构,该通道是通过突变生成的,起一个高度选择性“电压门控钙通道”的作用。这些结构显示,在小孔内有三个Ca2+结合点:两个高亲和性Ca2+结合点和一个低亲和性点——Ca2+在穿过小孔运动时占据后者。Ca2+离子在穿过该通道时保持近乎充分水合状态,这与教科书上所描述的充分脱水的金属离子结合到氨基酸侧链上或紧贴选择性过滤器内壁的骨干羰基基团上的情形是完全相反的。

Abstract 

Voltage-gated calcium (CaV) channels catalyse rapid, highly selective influx of Ca2+ into cells despite a 70-fold higher extracellular concentration of Na+. How CaV channels solve this fundamental biophysical problem remains unclear. Here we report physiological and crystallographic analyses of a calcium selectivity filter constructed in the homotetrameric bacterial NaV channel NaVAb. Our results reveal interactions of hydrated Ca2+ with two high-affinity Ca2+-binding sites followed by a third lower-affinity site that would coordinate Ca2+ as it moves inward. At the selectivity filter entry, Site 1 is formed by four carboxyl side chains, which have a critical role in determining Ca2+ selectivity. Four carboxyls plus four backbone carbonyls form Site 2, which is targeted by the blocking cations Cd2+ and Mn2+, with single occupancy. The lower-affinity Site 3 is formed by four backbone carbonyls alone, which mediate exit into the central cavity. This pore architecture suggests a conduction pathway involving transitions between two main states with one or two hydrated Ca2+ ions bound in the selectivity filter and supports a ‘knock-off’ mechanism of ion permeation through a stepwise-binding process. The multi-ion selectivity filter of our CaVAb model establishes a structural framework for understanding the mechanisms of ion selectivity and conductance by vertebrate CaV channels.

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