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The voltage-gated calcium channel Cav1.1 is engaged in the excitation-contraction coupling of skeletal muscles. The Cav1.1 complex consists of the pore-forming subunit α1 and auxiliary subunits α2δ, β, and γ. We report the structure of the rabbit Cav1.1 complex determined by single-particle cryo-electron microscopy. The four homologous repeats of the α1 subunit are arranged clockwise in the extracellular view. The γ subunit, whose structure resembles claudins, interacts with the voltage-sensing domain of repeat IV (VSDIV), whereas the cytosolic β subunit is located adjacent to VSDII of α1. The α2 subunit interacts with the extracellular loops of repeats I to III through its VWA and Cache1 domains. The structure reveals the architecture of a prototypical eukaryotic Cav channel and provides a framework for understanding the function and disease mechanisms of Cav and Nav channels. [ABSTRACT FROM AUTHOR]

RyR2 is a high-conductance intracellular calcium (Ca2+) channel that controls the release of Ca2+ from the sarco(endo)plasmic reticulum of a variety of cells. Here, we report the structures of RyR2 from porcine heart in both the open and closed states at near-atomic resolutions determined using single-particle electron cryomicroscopy. Structural comparison reveals a breathing motion of the overall cytoplasmic region resulted from the interdomain movements of amino-terminal domains (NTDs), Helical domains, and Handle domains, whereas almost no intradomain shifts are observed in these armadillo repeats–containing domains. Outward rotations of the Central domains, which integrate the conformational changes of the cytoplasmic region, lead to the dilation of the cytoplasmic gate through coupled motions. Our structural and mutational characterizations provide important insights into the gating and disease mechanism of RyRs. [ABSTRACT FROM AUTHOR]

Insulin-induced gene 1 (lnsig-1) and lnsig-2 are endoplasmic reticulum membrane-embedded sterol sensors that regulate the cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited. Here we report the high-resolution structures of MvlNS, an Insig homolog from Mycobacterium vanbaalenii. MvlNS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with TM3 and TM4 contributing to homotrimerization. The six TMs enclose a V-shaped cavity that can accommodate a diacylglycerol molecule. A homology-based structural model of human lnsig-2, together with biochemical characterizations, suggest that the central cavity of lnsig-2 accommodates 25-hydroxycholesterol, whereas TM3 and TM4 engage in Scap binding. These analyses provide an important framework for further functional and mechanistic understanding of Insig proteins and the sterol regulatory element-binding protein pathway. [ABSTRACT FROM AUTHOR]

The article discusses the highlights of a study published in the same issue to show the structural details of eukaryotic voltage-gated sodium (Nav) channels. Topics covered include the cryogenic electron microscopy or cryo-EM structure of NavPaS, the asymmetric selectivity filter vestibule of the Nav channels, and the voltage-sensing domains (VSD) formed by the eukaryotic Nav channels.