title: Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations.
abstract: 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.
authors: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1.
authors: Samuel K
authors: SK
authors: Lee
authors: Department of Molecular Genetics and Molecular Biochemistry, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA, 19140.
authors: Santhanam
authors: S
authors: Shanmughapriya
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada, L8S 4K1.
authors: Mac C Y
authors: MCY
authors: Mok
authors: Department of Molecular Genetics and Molecular Biochemistry, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA, 19140.
authors: Zhiwei
authors: Z
authors: Dong
authors: Department of Molecular Genetics and Molecular Biochemistry, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA, 19140.
authors: Dhanendra
authors: D
authors: Tomar
authors: Department of Molecular Genetics and Molecular Biochemistry, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA, 19140.
authors: Edmund
authors: E
authors: Carvalho
authors: Department of Molecular Genetics and Molecular Biochemistry, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA, 19140.
authors: Sudarsan
authors: S
authors: Rajan
authors: Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1.
authors: Murray S
authors: MS
authors: Junop
authors: Department of Molecular Genetics and Molecular Biochemistry, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA, 19140.
authors: Muniswamy
authors: M
authors: Madesh
authors: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1.
authors: Peter B
authors: PB
authors: Stathopulos
mesh_terms: D002118:Calcium / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D002413:Cations, Divalent / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation / Q000187:drug effects
chemical_list: D015220:Calcium Channels; D002413:Cations, Divalent; C034703:mitochondrial calcium uniporter; D008274:Magnesium; D002118:Calcium
keywords: MCU-regulating acidic patch; autoinhibition; calcium binding; magnesium binding; mitochondrial calcium uniporter; oligomerization; stability; structure