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8.A.45  The Essential MCU Regulator EMRE (EMRE) Family

The mitochondrial uniporter (1.A.77) is a highly selective calcium channel in the organelle's inner membrane. Its molecular components include the two EF-hand-containing calcium-binding proteins, mitochondrial calcium uptake 1 (MICU1) and MICU2 as well as the oligomeric pore-forming subunit, mitochondrial calcium uniporter (MCU) in animals.  Sancak et al. 2013 achieved a full molecular characterization of the uniporter holocomplex. Quantitative mass spectrometry of the affinity-purified complex revealed the presence of MICU1 and MICU2 (TC#8.A.44), MCU and its paralog MCUb (1.A.77), and an essential MCU regulator (EMRE), a 10-kilodalton protein with a single transmembrane domain. In its absence, uniporter channel activity was lost despite intact MCU expression and oligomerization. EMRE was required for the interaction of MCU with MICU1 and MICU2. Hence, EMRE is essential for in vivo uniporter current and bridges the calcium-sensing role of MICU1 and MICU2 with the calcium-conducting role of MCU (Sancak et al. 2013).  EMRE interacts with MCU and MICU via its transmembrane helices.  It maintains tight MICU regulation of the MCU pore, a role that involves EMRE binding to MICU1 using its conserved C-terminal polyaspartate tail. EMRE ensures that all transport-competent uniporters are tightly regulated, responding appropriately to a dynamic intracellular Ca2+ landscape (Tsai et al. 2016). It is essential for MCU activity in mice (Liu et al. 2020).

EMRE controls MCU activity via its transmembrane helix, while using an N-terminal PKP motif to strengthen binding with MCU. Opening of MCU requires hydrophobic interactions mediated by MCU residues near the pore's luminal end. Enhancing these interactions by single mutation allows human MCU to transport Ca2+ without EMRE. EMRE may thus facilitate MCU opening by stabilizing the open state in a conserved MCU gating mechanism, present also in non-metazoan MCU homologs (Van Keuren et al. 2020).

References associated with 8.A.45 family:

Liu, J.C., N.C. Syder, N.S. Ghorashi, T.B. Willingham, R.J. Parks, J. Sun, M.M. Fergusson, J. Liu, K.M. Holmström, S. Menazza, D.A. Springer, C. Liu, B. Glancy, T. Finkel, and E. Murphy. (2020). EMRE is essential for mitochondrial calcium uniporter activity in a mouse model. JCI Insight 5:. 32017711
MacEwen, M.J., A.L. Markhard, M. Bozbeyoglu, F. Bradford, O. Goldberger, V.K. Mootha, and Y. Sancak. (2020). Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU. Life Sci Alliance 3:. 32769116
Sancak, Y., A.L. Markhard, T. Kitami, E. Kovács-Bogdán, K.J. Kamer, N.D. Udeshi, S.A. Carr, D. Chaudhuri, D.E. Clapham, A.A. Li, S.E. Calvo, O. Goldberger, and V.K. Mootha. (2013). EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342: 1379-1382. 24231807
Tsai, M.F., C.B. Phillips, M. Ranaghan, C.W. Tsai, Y. Wu, C. Willliams, and C. Miller. (2016). Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex. Elife 5:. 27099988
Vais, H., R. Payne, U. Paudel, C. Li, and J.K. Foskett. (2020). Coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca uptake. Proc. Natl. Acad. Sci. USA 117: 21731-21739. 32801213
Van Keuren, A.M., C.W. Tsai, E. Balderas, M.X. Rodriguez, D. Chaudhuri, and M.F. Tsai. (2020). Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex. Cell Rep 33: 108486. 33296646