Filip Van Petegem, Professor, Department of Biochemistry & Molecular Biology, University of British Columbia, Canada, will give a talk titled, "Channelopathies at high resolution: Cryo-EM and crystallographic investigation of cardiac and skeletal muscle ion channels."

ABSTRACT:   The contraction of skeletal and cardiac muscle is a tightly orchestrated event that starts with an electrical signal: a depolarization of the plasma membrane.  Prior to contraction, this signal needs to be converted into a chemical signal: the release of calcium ions from the sarcoplasmic reticulum (SR). This process is mediated by two classes of ion channels: L-type voltage-gated calcium channels (CaVs), located in the T-tubular membrane, and Ryanodine Receptors (RyRs) in the SR membrane.  Their close proximity allows for functional and mechanical interactions depending on the exact cell type. The process requires an array of auxiliary proteins that bind and modulate both channels. The various components are targets for mutations that have been linked to severe genetic disorders, including myopathies, cardiac arrhythmias, and malignant hyperthermia. Using X-ray crystallography and cryo-EM, we have been solving high-resolution structures of various components in wild-type and disease mutant forms. Making use of a natural pig model, we purified disease mutant RyRs and solved a range of cryo-EM structures, which explain the gain-of-function phenotype associated with malignant hyperthermia.  Our results show that the exact effect is highly dependent on the roster of auxiliary proteins that are present in the complex.  STAC proteins and junctophilins are essential proteins that organize the cross-talk between RyRs and CaVs.  Their mutations have been linked to skeletal and cardiac myopathies, respectively. We explored their structure and how they mediate interactions with CaVs.