Structure of the voltage-gated calcium channel Ca(v)1.1 at 3.6 angstrom resolution

摘要

The voltage-gated calcium (Ca-v) channels convert membrane electrical signals to intracellular Ca2+-mediated events. Among the ten subtypes of Ca-v channel in mammals, Ca(v)1.1 is specified for the excitation-contraction coupling of skeletal muscles. Here we present the cryo-electron microscopy structure of the rabbit Ca(v)1.1 complex at a nominal resolution of 3.6 angstrom. The inner gate of the ion-conducting alpha 1-subunit is closed and all four voltage-sensing domains adopt an 'up' conformation, suggesting a potentially inactivated state. The extended extracellular loops of the pore domain, which are stabilized by multiple disulfide bonds, form a windowed dome above the selectivity filter. One side of the dome provides the docking site for the angstrom 2 delta-1-subunit, while the other side may attract cations through its negative surface potential. The intracellular I-II and III-IV linker helices interact with the beta(1a)-subunit and the carboxy-terminal domain of alpha 1, respectively. Classification of the particles yielded two additional reconstructions that reveal pronounced displacement of beta(1a) and adjacent elements in alpha 1. The atomic model of the Ca(v)1.1 complex establishes a foundation for mechanistic understanding of excitation-contraction coupling and provides a three-dimensional template for molecular interpretations of the functions and disease mechanisms of Ca-v and Na-v channels.