Research

Calcium (Ca²⁺) is an essential signaling messenger in every eukaryotic cell, regulating diverse and kinetically distinct cellular phenomena in health and disease. Sarco/endoplasmic reticulum (S/ER) luminal store-dependent Ca²⁺ influx through plasma membrane (PM) Ca²⁺ release activated Ca²⁺ (CRAC) channels drives cytosolic Ca²⁺ elevations. The molecular players that mediate this store-operated Ca²⁺ entry (SOCE) include the stromal interaction molecules (STIM)s, which sense changes in S/ER luminal Ca²⁺ levels, and the Orai proteins, which constitute the PM Ca²⁺ channel pore. Upon ER luminal Ca²⁺ store depletion, STIMs oligomerize and translocate to S/ER-PM junctions where they bind and activate the Orai channels, forming CRAC channel complexes. Our laboratory applies structural biology (i.e. solution NMR spectroscopy, X-ray crystallography, electron microscopy, in silico computational, etc.), biophysical methodologies (i.e. optical spectroscopies, calorimetry, chromatography, light/X-ray scattering, etc.) and live cell assessments (i.e. TIRF, epifluorescence, FRET, confocal, Ca²⁺ imaging, etc.) combined with pharmacological tools to investigate the molecular mechanisms regulating STIM/Orai function and the modes of dysfunction associated with disease.

Mitochondria are widely recognized as cellular "power plants" due to the high production of ATP. However, mitochondrial Ca²⁺ uptake can shape cytosolic Ca²⁺ signals, which underlie myriad signaling pathways. Remarkably, mitochondria Ca²⁺ uptake not only regulates the enzymes that generate ATP, but also drives critical cell death pathways that maintain health and lead to disease. Thus, we are examining the relationships between the structures and functions of the protein machinery involved in regulating mitochondrial Ca²⁺ uptake. Understanding the molecular and structural mechanisms driving the function of these proteins will expose novel avenues for the modulation of mitochondrial Ca²⁺uptake in the treatment of heart disease and cancer, which account for ~50 % of all Canadian deaths annually.

Keywords

calcium signaling; molecular pharmacology; structural biology; solution nuclear magnetic resonance spectroscopy; live cell imaging; X-ray crystallography; calorimetry; protein folding; biomolecular thermodynamics; computational biology; protein structure and function; protein-protein interactions; protein allostery; ion channels; protein dynamics; light scattering; optical spectroscopy; heart disease; cancer; immunodeficiency