Structural basis for Ca2+ selectivity of a voltage-gated calcium channel

Article

关键词: CRYSTAL-STRUCTURE;    ION SELECTIVITY;    SODIUM-CHANNEL;    CONCERTED ACTION;    FROG-MUSCLE;    PERMEATION;    CONDUCTION;    LOCUS;    PORE;    BACTERIORHODOPSIN;   

DOI  :  10.1038/nature12775

来源: SCIE

【 摘 要 】

Voltage-gated calcium (Ca-V) channels catalyse rapid, highly selective influx of Ca2+ into cells despite a 70-fold higher extracellular concentration of Na+. How Ca-V 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 Na-V channel Na(V)Ab. 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 Ca(V)Ab model establishes a structural framework for understanding the mechanisms of ion selectivity and conductance by vertebrate Ca-V channels.

【 授权许可】

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