The structural biology of ryanodine receptors

Abstract

Ryanodine receptors are ion channels that allow for the release of Ca 2+ from the endoplasmic or sarcoplasmic reticulum. They are expressed in many different cell types but are best known for their predominance in skeletal and cardiac myocytes, where they are directly involved in excitation-contraction coupling. With molecular weights exceeding 2 MDa, Ryanodine Receptors are the largest ion channels known to date and present major challenges for structural biology. Since their discovery in the 1980s, significant progress has been made in understanding their behaviour through multiple structural methods. Cryo-electron microscopy reconstructions of intact channels depict a mushroom-shaped structure with a large cytoplasmic region that presents many binding sites for regulatory molecules. This region undergoes significant motions during opening and closing of the channel, demonstrating that the Ryanodine Receptor is a bona fide allosteric protein. High-resolution structures through X-ray crystallography and NMR currently cover ~11% of the entire protein. The combination of high-and low-resolution methods allows us to build pseudo-atomic models. Here we present an overview of the electron microscopy, NMR, and crystallographic analyses of this membrane protein giant. calcium release, excitation-contraction coupling, genetic disease, structural biology, calcium release channel, ion channel

Crystal structures of wild type and disease mutant forms of the ryanodine receptor SPRY2 domain

“…Cryo-electron microscopy (cryo-EM) studies have shown that the RyRs form tetrameric assemblies that resemble the shape of a mushroom [7][8][9][10] : the stalk region is thought to traverse the membrane of the ER or SR, and the large cap is located entirely in the cytosol. The cap regulates the ability of the channel to open or close, turning RyRs into enormous allosteric membrane proteins 11 .…”

Morphogenesis of T-tubules in heart cells: the role of junctophilin-2

“…TTs are widely distributed in cardiac cells and meet the sarcoplasmic reticulum (SR) with ~12 nm junctional clefts, forming structural units for calcium signaling, known as couplons [8,9]. During E-C coupling, the Ca 2+ influx through L-type calcium channels on the TT activates the ryanodine receptor (RyR) calcium release channels on the adjacent SR to initiate a calcium transient [10,11]. This Ca 2+ -induced Ca 2+ release (CICR) process drives the contraction of cardiac cells [12,13].…”

Progress in protein structure and function studies in China during 2010–2011

“…Lan et al [56] reviewed the expression of proteins involved in iron metabolism in kidneys, such as transferring receptor-1, divalent metal transporter-1, ferroportin-1, iron regulatory protein and hepcidin. Kimlicka and van Petegem [57] reviewed recent studies on the structural biology of ryanodine receptors. Ryanodien receptors are large ion channels that facilitate the release of calcium cations from the endoplasmic or sarcoplasmic reticulum.…”