Mitochondrial Ca2+ uptake, a process crucial for bioenergetics and Ca2+ signaling, is catalyzed by the mitochondrial calcium uniporter. The uniporter is a multi-subunit Ca2+-activated Ca2+ channel, with the Ca2+ pore formed by the MCU protein and Ca2+-dependent activation mediated by MICU subunits. Recently, a mitochondrial inner membrane protein EMRE was identified as a uniporter subunit absolutely required for Ca2+ permeation. However, the molecular mechanism and regulatory purpose of EMRE remain largely unexplored. Here, we determine the transmembrane orientation of EMRE, and show that its known MCU-activating function is mediated by the interaction of transmembrane helices from both proteins. We also reveal a second function of EMRE: to maintain tight MICU regulation of the MCU pore, a role that requires EMRE to bind MICU1 using its conserved C-terminal polyaspartate tail. This dual functionality of EMRE ensures that all transport-competent uniporters are tightly regulated, responding appropriately to a dynamic intracellular Ca2+ landscape.
- David E Clapham, Howard Hughes Medical Institute, Boston Children's Hospital, United States
- Received: February 25, 2016
- Accepted: April 19, 2016
- Accepted Manuscript published: April 21, 2016 (version 1)
- Accepted Manuscript updated: May 6, 2016 (version 2)
- Version of Record published: June 3, 2016 (version 3)
- Version of Record updated: June 6, 2016 (version 4)
- Version of Record updated: March 2, 2017 (version 5)
© 2016, Tsai et al.
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