Master of Science
Physiology and Pharmacology
Stathopulos, Peter B.
Mitochondria are primarily appreciated for the generation of adenosine triphosphate (ATP), a chemical store of energy required by all cells. These organelles, however, also play key roles in apoptosis, autophagy and shaping cytosolic calcium (Ca2+) signaling via Ca2+ uptake into the mitochondrial matrix. This Ca2+ uptake is mediated chiefly via the mitochondrial Ca2+ uniporter (MCU), an inner mitochondrial membrane protein that oligomerizes to form a Ca2+ selective pore. MCU is regulated by several protein binding partners, including the recently identified MCU regulator-1 (MCUR1). MCUR1 stabilizes a higher order MCU heterocomplex through interactions with MCU and other protein regulators. I hypothesize that the evolutionarily conserved matrix region of MCUR1 contains domains vital for protein and ion interactions which regulate MCU complex formation and function. My biophysical characterization of the MCUR1 matrix domain which includes the coiled-coil domains (i.e. residues 161-338) revealed that this conserved region forms a highly a-helical and self-associated multimer that is conformationally sensitive to divalent cations. Additionally, my solution nuclear magnetic resonance spectroscopy-driven structural elucidation of the MCUR1 matrix region which excludes the coiled-coil domains (i.e. residues 161-209) revealed that this region of MCUR1 forms a compact triple helix which is structurally homologous to the HdeB acid stress chaperone protein despite very low sequence identity. These findings represent the first structural data on MCUR1 and provide a strong framework for future functional studies to assess the significance of MCUR1 oligomerization and ion sensitivity on MCU heterocomplex assembly and activity which has been implicated in numerous cancers as well as metabolic, neurodegenerative and cardiovascular disorders.
Siddiqui, Naveed, "The mitochondrial calcium uniporter regulator 1 (MCUR1) matrix domain is a self-associated multimer sensitive to divalent cations" (2018). Electronic Thesis and Dissertation Repository. 5912.