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

Lin Tang, Tamer M. Gamal El-Din, Jian Payandeh, Gilbert Q. Martinez, Teresa M. Heard, Todd Scheuer, Ning Zheng () and William A. Catterall ()
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Lin Tang: University of Washington, Seattle, Washington 98195, USA
Tamer M. Gamal El-Din: University of Washington, Seattle, Washington 98195, USA
Jian Payandeh: University of Washington, Seattle, Washington 98195, USA
Gilbert Q. Martinez: University of Washington, Seattle, Washington 98195, USA
Teresa M. Heard: University of Washington, Seattle, Washington 98195, USA
Todd Scheuer: University of Washington, Seattle, Washington 98195, USA
Ning Zheng: University of Washington, Seattle, Washington 98195, USA
William A. Catterall: University of Washington, Seattle, Washington 98195, USA

Nature, 2014, vol. 505, issue 7481, 56-61

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature12775

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