Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations

Samuel K. Lee, Santhanam Shanmughapriya, Mac C.Y. Mok, Zhiwei Dong, Dhanendra Tomar, Edmund Carvalho, Sudarsan Rajan, Murray S. Junop, Madesh Muniswamy, Peter B. Stathopulos

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Calcium (Ca2+) flux into the matrix is tightly controlled by the mitochondrial 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 β-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 Ca2+-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 Mg2+ and Ca2+ binding.

Original languageEnglish (US)
Pages (from-to)1157-1169
Number of pages13
JournalCell Chemical Biology
Volume23
Issue number9
DOIs
StatePublished - Sep 22 2016
Externally publishedYes

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Keywords

  • autoinhibition
  • calcium binding
  • magnesium binding
  • MCU-regulating acidic patch
  • mitochondrial calcium uniporter
  • oligomerization
  • stability
  • structure

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Lee, S. K., Shanmughapriya, S., Mok, M. C. Y., Dong, Z., Tomar, D., Carvalho, E., Rajan, S., Junop, M. S., Muniswamy, M., & Stathopulos, P. B. (2016). Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations. Cell Chemical Biology, 23(9), 1157-1169. https://doi.org/10.1016/j.chembiol.2016.07.012