TY - JOUR TI - Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex AU - Tsai, Ming-Feng AU - Phillips, Charles B AU - Ranaghan, Matthew AU - Tsai, Chen-Wei AU - Wu, Yujiao AU - Williams, Carole AU - Miller, Christopher A2 - Clapham, David E VL - 5 PY - 2016 DA - 2016/04/21 SP - e15545 C1 - eLife 2016;5:e15545 DO - 10.7554/eLife.15545 UR - https://doi.org/10.7554/eLife.15545 AB - 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. KW - calcium transport KW - MCU KW - EMRE KW - ion channel KW - mitochondria JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -