1. Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations.
- Author
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Lee, Samuel K., Shanmughapriya, Santhanam, Mok, Mac C.Y., Dong, Zhiwei, Tomar, Dhanendra, Carvalho, Edmund, Rajan, Sudarsan, Junop, Murray S., Madesh, Muniswamy, and Stathopulos, Peter B.
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MITOCHONDRIA , *CALCIUM ions , *CELL death , *BIOENERGETICS , *N-terminal residues , *ACQUISITION of data - Abstract
Summary Calcium (Ca 2+ ) flux into the matrix is tightly controlled by the mitochondrial Ca 2+ uniporter (MCU) due to vital roles in cell death and bioenergetics. However, the precise atomic mechanisms of MCU regulation remain unclear. Here, we solved the crystal structure of the N-terminal matrix domain of human MCU, revealing a β-grasp-like fold with a cluster of negatively charged residues that interacts with divalent cations. Binding of Ca 2+ or Mg 2+ destabilizes and shifts the self-association equilibrium of the domain toward monomer. Mutational disruption of the acidic face weakens oligomerization of the isolated matrix domain and full-length human protein similar to cation binding and markedly decreases MCU activity. Moreover, mitochondrial Mg 2+ loading or blockade of mitochondrial Ca 2+ extrusion suppresses MCU Ca 2+ -uptake rates. Collectively, our data reveal that the β-grasp-like matrix region harbors an MCU-regulating acidic patch that inhibits human MCU activity in response to Mg 2+ and Ca 2+ binding. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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