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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 & William A. Catterall
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.
