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Peter Stathopulos

Why Science?
I completed a cooperative undergraduate degree in Biology, which gave me the opportunity to work in industry, academia and government. I found that I genuinely appreciated work terms that involved basic scientific research. This cooperative experience inspired me to pursue research as a career. Being able to contribute to scientific knowledge and expose the elegance of natural processes has driven me ever since. There is a feeling of accomplishment after answering a scientific question and having peers read, cite and use your work to meet their own research goals.

I subsequently earned a Master’s degree in Pharmacology and Toxicology where I studied how the transport of L-arginine changes in the vasculature of an animal model of heart disease. Finally, I completed my PhD studying the effects of amyotrophic lateral sclerosis (ALS)-associated mutations on the folding and stability of superoxide dismutase. At this time, I realized that I needed atomic level pictures of the proteins I was studying to precisely understand how they function. Thus, I decided to pursue post-doctoral training in structural biology at the University of Toronto and the Princess Margaret Cancer Centre. Structural biology is a field of science where atomic-level depictions of proteins are used to reveal their molecular mechanisms of action. Because changes in protein structure underlie myriad disease states, resolving structures of proteins with mutations linked to disease can help us understand why the protein is dysfunctional and provide novel treatment strategies. During my post-doctoral training, I also gained an appreciation for the universality of calcium signaling, which underlies all cellular processes that help us grow and maintain our health, as well as lead to disease.

Research Goals
My laboratory aims to apply structural biology approaches to reveal the molecular mechanisms driving calcium signaling processes in health and diseased states including heart disease, cancer and immunodeficiency. We integrate structural biology with a host of biophysical, pharmacological and live cell methodologies in an effort to understand the relationship between structure and function of critical calcium signaling proteins. Ultimately, we use this structure-function data for the identification of new drug binding targets with the potential to modulate these pathways, maintain health and treat disease.

Specific Research Interests
1.  How Stromal Interaction Molecules Regulate Orai1 Calcium Channel Function
Calcium (Ca ²⁺) is an essential signaling messenger in every eukaryotic cell, regulating diverse and kinetically distinct cellular phenomena in health and disease. Sarco/endoplasmic reticulum (SR/ER) luminal store-dependent Ca ²⁺ influx through plasma membrane (PM) Ca ²⁺ release activated Ca ²⁺ (CRAC) channels is a vital Ca ²⁺ entry pathway, mediating sustained cytosolic Ca ²⁺elevations. The molecular players that mediate this store-operated Ca ²⁺ entry (SOCE) include the stromal interaction molecules (STIM)s, which sense changes in SR/ER luminal Ca ²⁺ levels, and the Orai proteins, which constitute the PM Ca ²⁺ channel pore. Upon ER luminal Ca ²⁺ store depletion, STIMs oligomerize and translocate to the SR/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 simulations), biophysical methodologies (i.e. optical spectroscopies, calorimetry, chromatography, light/X-ray scattering, etc.) and live cell assessments (i.e. TIRF, epifluorescence, FRET, confocal, Ca ²⁺ imaging, etc.) combined with pharmacological tools to investigate the molecular mechanisms regulating STIM/Orai function and the modes of dysfunction associated with disease.

2.  How Mitochondrial Calcium Handling Machinery Function in Health and Disease
Mitochondria are widely recognized as cellular power plants due to the production of ATP. Mitochondrial Ca ²⁺uptake can shape cytosolic Ca ²⁺ signals, which underlie myriad signaling pathways. Remarkably, mitochondria Ca ²⁺ 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 Ca ²⁺ uptake. Understanding the molecular and structural mechanisms driving the function of these proteins will expose novel avenues for the modulation of mitochondrial Ca ²⁺uptake in the treatment of heart disease and cancer, which account for ~50 % of all Canadian deaths annually.

Most Rewarding Moments
We have many Western students interested in entering health-related professional schools, and as a supervisor, it is gratifying to help trainees succeed in meeting these challenging goals. For my students who are interested in establishing a career in research, I remind them that if they learn something new each day about their project (even from failed experiments), they are on track for success. It is tremendously rewarding helping students earn their first peer-reviewed publications.

Publications:
See all my publications on Pubmed.

Highlighted Publications:
Lin, Q-T. and Stathopulos P.B. (2019). Molecular mechanisms of leucine zipper EF-hand containing transmembrane protein-1 function in health and disease. Int J Mol Sci. 20(2). pii: E286. Link to article

Stathopulos, P.B. and Ikura, M. (2019). Does stromal interaction molecule-1 have five senses? Cell Calcium . 77:79-80. Link to article

Chung, S., Zhang, M. and Stathopulos, P.B. (2018). The 2beta splice variation alters the structure and function of the stromal interaction molecule coiled-coil domains. Int J Mol Sci . 19(11). pii: E3316. Link to article

Zhu, J., Lu, X., Feng, Q. and Stathopulos, P.B. (2018). A charge sensing region in the STIM1 luminal domain confers stabilization-mediated inhibition of SOCE in response to S-nitrosylation. J Biol Chem . 293(23):8900-8911. Link to article

Choi, Y.J., Zhao, Y., Bhattacharya, M. and Stathopulos, P.B. (2017). Structural perturbations induced by Asn131 and Asn171 glycosylation converge within the EFSAM core and enhance stromal interaction molecule-1 mediated store operated calcium entry. Biochim Biophys Acta ( BBA) – Mol Cell Res . 1864(6):1054-1063. Link to article
NOTE: Selected as journal issue cover art focus. 

Lee, S.K., Shanmughapriya, S., Mok, M.C.Y., Dong, Z., Rajan, S., Junop, M., Madesh, M. and Stathopulos, P.B.(2016). The mitochondrial calcium uniporter is autoregulated by cation binding to a beta-grasp-like matrix domain. Cell Chem Biol . 23(9):1157-69. Link to article