X-ray and cryo-EM structures of the mitochondrial calcium uniporter

Chao Fan, Minrui Fan, Benjamin J. Orlando, Nathan M. Fastman, Jinru Zhang, Yan Xu, Melissa G. Chambers, Xiaofang Xu, Kay Perry, Maofu Liao () and Liang Feng ()
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Chao Fan: Stanford University School of Medicine
Minrui Fan: Stanford University School of Medicine
Benjamin J. Orlando: Harvard Medical School
Nathan M. Fastman: Stanford University School of Medicine
Jinru Zhang: Stanford University School of Medicine
Yan Xu: Stanford University School of Medicine
Melissa G. Chambers: Harvard Medical School
Xiaofang Xu: Stanford University School of Medicine
Kay Perry: Cornell University, Argonne National Laboratory
Maofu Liao: Harvard Medical School
Liang Feng: Stanford University School of Medicine

Nature, 2018, vol. 559, issue 7715, 575-579

Abstract: Abstract Mitochondrial calcium uptake is critical for regulating ATP production, intracellular calcium signalling, and cell death. This uptake is mediated by a highly selective calcium channel called the mitochondrial calcium uniporter (MCU). Here, we determined the structures of the pore-forming MCU proteins from two fungi by X-ray crystallography and single-particle cryo-electron microscopy. The stoichiometry, overall architecture, and individual subunit structure differed markedly from those described in the recent nuclear magnetic resonance structure of Caenorhabditis elegans MCU. We observed a dimer-of-dimer architecture across species and chemical environments, which was corroborated by biochemical experiments. Structural analyses and functional characterization uncovered the roles of key residues in the pore. These results reveal a new ion channel architecture, provide insights into calcium coordination, selectivity and conduction, and establish a structural framework for understanding the mechanism of mitochondrial calcium uniporter function.

Date: 2018
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DOI: 10.1038/s41586-018-0330-9

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