BME Seminar Series: Dr. Filip Van Petegem, University of British Columbia
In-person 2000 Fontana Labs
Filip Van Petegem, PhD
Department of Biochemistry and Molecular Biology
University of British Columbia
"Cryo-EM and crystallographic investigation of ion channel complexes involved in muscle excitation-contraction coupling"
The contraction of cardiac and skeletal muscle relies on the coordinated release of Calcium ions stored in the Sarcoplasmic Reticulum (SR). This release is a highly coordinated event that mostly relies on the communication between two types of ion channels: L-type voltage-gated calcium channels in the plasma membrane and Ryanodine Receptors in the SR. Their communication requires physical proximity and, in the case of skeletal muscle, also mechanical interactions. Multiple auxiliary proteins assist in this process, including Junctophilin and STAC proteins. All components are also targets for a range of debilitating disease-causing mutations that cause inherited arrhythmias, myopathies, and malignant hyperthermia. In addition, post-translational modifications can significantly alter their functions and contribute to acquired disorders including atrial fibrillation and heart failure. We study the normal physiology and pathophysiology of various components involved in this coupling using a combination of X-ray crystallography, cryo-EM, and various biophysical methods. For example, we analyzed the effect of pathogenic mutations of the Ryanodine Receptor. Cryo-EM structures show that mutations can cause large conformational changes that result in facilitated channel opening, in line with electrophysiological measurements we carry out on the same sample. We also find that auxiliary proteins such as calmodulin can significantly alter the structural and functional outcome of a disease mutation.
Structure and function of ion channels, membrane proteins involved in generating electrical signals in living organisms. We study their 3D structure via X-ray Crystallography and cryo-electron microscopy, and study their function via electrophysiology. Our main focus is on channels involved in the excitation-contraction coupling in muscle tissue. We also study the various diseases associated with these channels, including skeletal muscle disorders and cardiac arrhythmias.