PH.D. University of Waterloo
M.Sc. The University of Western Ontario
B.Sc. University of Waterloo
Office: Medical Sciences Building, Room 232
p. 519.661.2111 x. 83238
Lab: Medical Sciences Building, Room 219
p. 519.661.2111 x. 82812
See Publications by Peter Stathopulos on PubMed
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 (SR/ER) luminal store-dependent Ca2+ influx through plasma membrane (PM) Ca2+ release activated Ca2+ (CRAC) channels is a vital Ca2+ entry pathway mediating sustained 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 SR/ER luminal Ca2+ levels and the Orai proteins which constitute the PM Ca2+ channel pore. Upon luminal Ca2+ store depletion, STIMs oligomerize and translocate to the SR/ER-PM junctions where they recruit and activate the Orai channels, forming a CRAC channel complex. My research applies structural biology (i.e. solution nuclear magnetic resonance spectroscopy and X-ray crystallography), biophysical methodologies (i.e. optical spectroscopies, calorimetry, chromatography, light/X-ray scattering, etc.) and live cell microscopy (i.e. TIRF, epifluorescence, FRET, confocal) to investigate the molecular and biochemical pharmacology driving the mechanisms of STIM/Orai cellular signaling and the modes of dysfunction in patho-physiological circumstances.
Inter-compartmental transfer and modulation of Ca2+ levels are not exclusive to the extracellular space, cytosol and SR/ER lumen. Although mitochondria are widely recognized as cellular power plants, the buffering impact of mitochondrial Ca2+ uptake can shape the cytosolic Ca2+ oscillations and transients involved in numerous physiological processes. The mitochondrial calcium uptake 1 (MICU1) single pass transmembrane protein is a critical modulator of a high capacity mitochondrial Ca2+ uptake system, regulating the activity of the mitochondrial Ca2+ uniporter (MCU), a dual spanning transmembrane protein forming an ion channel located on the inner mitochondrial membrane. Intriguing similarities can be drawn between MICU1-MCU and STIM-Orai signaling: first, each system employs a regulatory component which is sensitive to Ca2+ (i.e. STIM versus MICU1); second, these regulatory molecules modulate Ca2+ channel activity of a respective pore forming protein (i.e. Orai versus MCU). I am interested in examining the relationships between the structures and functions of the MICU1 and MCU Ca2+ signaling components using the aforementioned high resolution structural probes, biophysical approaches and live cell analyses.
Stathopulos PB, Ikura M. (2013). Structure and Function of Endoplasmic Reticulum STIM Calcium Sensors. Curr Top Membr. v71:59-93.
Stathopulos PB, Seo MD, Enomoto M, Amador FJ, Ishiyama N, Ikura M. (2012). Themes and variations in ER/SR calcium release channels: structure and function. Physiology (Bethesda). v27(6):331-42.
Seo MD, Velamakanni S, Ishiyama N, Stathopulos PB, Rossi AM, Khan SA, Dale P, Li C, Ames JB, Ikura M, Taylor CW. (2012). Structural and functional conservation of key domains in InsP3 and ryanodine receptors. Nature. v483(7387):108-12.
Zheng L, Stathopulos PB, Schindl R, Li GY, Romanin C, Ikura M. (2011). Auto-inhibitory role of the EF-SAM domain of STIM proteins in store-operated calcium entry. Proc Natl Acad Sci U S A. v108(4):1337-42.
Stathopulos PB, Zheng L, Ikura M. (2009). Stromal interaction molecule (STIM) 1 and STIM2 calcium sensing regions exhibit distinct unfolding and oligomerization kinetics. J Biol Chem. v284(2):728-32.
Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M. (2008). Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell. v135(1):110-22.