Journal
CELL CHEMICAL BIOLOGY
Volume 23, Issue 9, Pages 1157-1169Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2016.07.012
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Funding
- Natural Sciences and Engineering Research Council of Canada [05239]
- Canadian Foundation for Innovation/Ontario Research Fund
- Canadian Institutes of Health Research [MOP 89903]
- NIH [R01GM109882, R01HL086699, R01HL119306, 1S10RR027327]
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Calcium (Ca2+) flux into the matrix is tightly controlled by themitochondrial Ca2+ 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 beta-grasp-like fold with a cluster of negatively charged residues that interacts with divalent cations. Binding of Ca2+ or Mg2+ 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 Mg2+ loading or blockade of mitochondrial Ca2+ extrusion suppresses MCU Ca(2+)uptake rates. Collectively, our data reveal that the b-grasp-like matrix region harbors an MCU-regulating acidic patch that inhibits human MCU activity in response to Mg2+ and Ca2+ binding.
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