The Mitochondrial Calcium Uniporter Is Autoregulated by Cation Binding to the β-Grasp-Like Matrix Domain

Author

Samuel K. Lee, The University of Western OntarioFollow

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Dr. Peter Stathopulos

Abstract

Mitochondrial calcium (Ca²⁺) uptake plays fundamental roles in various signaling processes. Entry of Ca²⁺ into the mitochondrial matrix is tightly controlled by the mitochondrial Ca²⁺ uniporter (MCU) in a higher order complex regulated by inter- and intra-molecular protein-protein interactions. However, the precise mechanisms controlling MCU function and regulation remain largely unknown. I identified a well-folded N-terminal MCU region from residues 72-189, and its crystal structure revealed a β-grasp-like fold with a cluster of acidic residues that facilitates interactions with dibasic cations. Binding of Ca²⁺ or Mg²⁺ destabilize this fold and shift the protein towards monomer. Single mutants disrupting the acidic face reduced the cation sensitivity in vitro. Together, my data reveal that the β-grasp-like matrix region of MCU harbors a distinct acidic patch that modulates stability and protein-protein interaction equilibria in response to Mg²⁺ and Ca²⁺ binding, suggesting that these matrix cations play an important role in controlling MCU activity.

Recommended Citation

Lee, Samuel K., "The Mitochondrial Calcium Uniporter Is Autoregulated by Cation Binding to the β-Grasp-Like Matrix Domain" (2016). Electronic Thesis and Dissertation Repository. 3827.
https://ir.lib.uwo.ca/etd/3827