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Muscle Excitation-Contraction Coupling: Employing X-Ray Crystallography And Cryo-EM To Investigate Calcium-Selective Ion Channels

Date: 
Tuesday, December 1, 2020 - 12:45 to 14:00
Speaker: 
Dr. Filip Van Petegem
Affiliation: 
Dept. of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia
Event Category: 
LMC - Lectures in Modern Chemistry
Host: 
Dr. Lawrence McIntosh
Location: 
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Abstract:

Calcium ions play vital roles throughout the human body. In cardiac and skeletal muscle cells, an increase in the cytosolic Ca2+ concentration leads to contraction.  The entry is initiated via an electrical signal, the depolarization of the plasma membrane, which leads to the opening of voltage-gated calcium channels (CaV).  This is rapidly followed by the release of more Ca2+ from the Sarcoplasmic Reticulum, through another channel known as the Ryanodine Receptor (RyR). Together, CaVs and RyRs are part of a larger complex that includes several auxiliary proteins.  Both are targets for hundreds of disease-associated mutations that cause cardiac arrhythmia, muscle weakness, and malignant hyperthermia.  Using cryo-EM and X-ray crystallography, we have dissected the architecture of both channels, analyzing how disease mutations affect their structure and function. A key question is how both channels communicate. In skeletal muscle in particular, conformational changes in the CaV channels are thought to be transmitted mechanically to the RyRs. This process remains highly enigmatic, but it is known to rely on the action of a small protein known as STAC3. We utilized calorimetry, electrophysiology, and structural biology methods to understand how STAC proteins associate with this complex. Finally, a major role is played by Calmodulin, a small Ca2+ sensing protein that can fine-tune the functional properties of both CaVs and RyRs. Mutations in the genes that encode calmodulin give rise to some of the most severe forms of cardiac arrhythmia. We found that small point mutations can have huge effects on its structural and biochemical properties and that the disease mechanisms are dependent on the precise mutation.