Cryo-EM structure of a fungal mitochondrial calcium uniporter

Abstract

The mitochondrial calcium uniporter (MCU) is a highly selective calcium channel localized to the inner mitochondrial membrane. Here, we describe the structure of an MCU orthologue from the fungus Neosartorya fischeri (NfMCU) determined to 3.8 Å resolution by phase-plate cryo-electron microscopy. The channel is a homotetramer with two-fold symmetry in its amino-terminal domain (NTD) that adopts a similar structure to that of human MCU. The NTD assembles as a dimer of dimers to form a tetrameric ring that connects to the transmembrane domain through an elongated coiled-coil domain. The ion-conducting pore domain maintains four-fold symmetry, with the selectivity filter positioned at the start of the pore-forming TM2 helix. The aspartate and glutamate sidechains of the conserved DIME motif are oriented towards the central axis and separated by one helical turn. The structure of NfMCU offers insights into channel assembly, selective calcium permeation, and inhibitor binding.

Chloroplast Calcium Signaling in the Spotlight

“…]. The structure of MCU homologs from various organisms has been recently solved: 1) from Fusarium graminearum and Metarhizium acridum revealing a dimer assembly of MCU (Fan et al, 2018); 2) from Neurospora crassa (Yoo et al, 2018); 3) from Neosartorya fischeri (Nguyen et al, 2018b); and from 4) zebrafish and Cyphellophora europaea (Baradaran et al, 2018). All these homologues share high sequence similarity in their transmembrane domains, show a similar pore architecture and a high structural similarity of the NTDs (despite relatively low sequence homology).…”

Why don't mice lacking the mitochondrial Ca2+ uniporter experience an energy crisis?

“…An earlier structural study indicates that C. elegans MCU forms pentamers for Ca 2+ transportation (Oxenoid et al 2016). Most recently, cryo-EM and X-ray structures of fungi MCU indicate a tetrameric architecture (Fan et al 2018;Nguyen et al 2018;Yoo et al 2018).…”

Redox Stability Controls the Cellular Uptake and Activity of Ruthenium‐Based Inhibitors of the Mitochondrial Calcium Uniporter (MCU)

“…[1] Uptake of these ions by the mitochondria is mediated by the highly selective and inwardly rectifying channel known as the mitochondrial calcium uniporter (MCU). [2] This protein resides in the inner mitochondrial membrane (IMM) and forms atetrameric,dimer of dimers type of assembly, [3][4][5][6] with both the N-and C-terminal domains located within the mitochondrial matrix. [7,8] Although mitochondrial Ca 2+ uptake through the MCU is needed for proper cellular function, dysregulation of this process through mitochondrial calcium overload gives rise to cell damage and death.…”