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bioRxiv · 10.1101/637918

Molecular basis of EMRE-dependence of the human mitochondrial calcium uniporter

MacEwen, M. J. S.·Markhard, A. L.·Bozbeyoglu, M.·Bradford, F.·Goldberger, O.·Mootha, V. K.·Sancak, Y.
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Abstract

The mitochondrial uniporter is calcium-activated calcium channel complex critical for cellular signaling and bioenergetics. MCU, the pore-forming subunit of the uniporter, contains two transmembrane domains and is found in all major eukaryotic taxa. In amoeba and fungi, MCU homologs are sufficient to form a functional calcium channel, whereas human MCU exhibits a strict requirement for the metazoan-specific, single-pass transmembrane protein EMRE for conductance. Here, we exploit this evolutionary divergence to decipher the molecular basis of the human MCUs dependence on EMRE. By systematically generating chimeric proteins that consist of EMRE-independent D. discoideum MCU (DdMCU) and H. sapiens MCU (HsMCU), we converged on a stretch of 10 amino acids in DdMCU that can be transplanted to HsMCU to render it EMRE-dependent. We call this region in human MCU the EMRE-dependence domain (EDD). Crosslinking experiments show that HsEMRE directly interacts with MCU at both of its transmembrane domains as well as the EDD. Based on previously published structures of fungal MCU homologs, the EDD segment is located distal to the calcium pores selectivity filter and appears flexible. We propose that EMRE stabilizes EDD of MCU, permitting both channel opening and calcium conductance

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MacEwen, M. J. S., Markhard, A. L., Bozbeyoglu, M., Bradford, F., Goldberger, O., Mootha, V. K., Sancak, Y.. 2019-05-14. Molecular basis of EMRE-dependence of the human mitochondrial calcium uniporter. https://doi.org/10.1101/637918

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