Architecture of the mitochondrial calcium uniporter

The structure of the core region of the mitochondrial calcium uniporter (MCU) is determined by NMR and electron microscopy, revealing that MCU is a homo-pentamer with a specific transmembrane helix forming a hydrophilic pore across the membrane, and representing one of the largest membrane protein structures characterized by NMR spectroscopy. Mitochondrial calcium uniporter structure Many mitochondria use an inner membrane transporter, called the uniporter, to uptake and buffer large amounts of Ca 2+ . The MCU (mitochondrial calcium uniporter) is the pore-forming and Ca 2+ -conducting subunit of the uniporter, but its primary sequence does not resemble any calcium channel known to date. These authors report the structure of the core region of the MCU using nuclear magnetic resonance spectroscopy and electron microscopy. They show that the MCU is a homo-oligomer with a specific transmembrane helix forming a hydrophilic pore across the membrane. In addition to having a previously unknown channel architecture, the MCU is one of the largest structures to have been characterized by NMR spectroscopy. Mitochondria from many eukaryotic clades take up large amounts of calcium (Ca 2+ ) via an inner membrane transporter called the uniporter. Transport by the uniporter is membrane potential dependent and sensitive to ruthenium red or its derivative Ru360 (ref. 1 ). Electrophysiological studies have shown that the uniporter is an ion channel with remarkably high conductance and selectivity 2 . Ca 2+ entry into mitochondria is also known to activate the tricarboxylic acid cycle and seems to be crucial for matching the production of ATP in mitochondria with its cytosolic demand 3 . Mitochondrial calcium uniporter (MCU) is the pore-forming and Ca 2+ -conducting subunit of the uniporter holocomplex, but its primary sequence does not resemble any calcium channel studied to date. Here we report the structure of the pore domain of MCU from Caenorhabditis elegans , determined using nuclear magnetic resonance (NMR) and electron microscopy (EM). MCU is a homo-oligomer in which the second transmembrane helix forms a hydrophilic pore across the membrane. The channel assembly represents a new solution of ion channel architecture, and is stabilized by a coiled-coil motif protruding into the mitochondrial matrix. The critical DXXE motif forms the pore entrance, which features two carboxylate rings; based on the ring dimensions and functional mutagenesis, these rings appear to form th