Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex.
Mitochondrial Ca(2+) uptake, a process crucial for bioenergetics and Ca(2+) signaling, is catalyzed by the mitochondrial calcium uniporter. The uniporter is a multi-subunit Ca(2+)-activated Ca(2+) channel, with the Ca(2+) pore formed by the MCU protein and Ca(2+)-dependent activation mediated by MICU subunits. Recently, a mitochondrial inner membrane protein EMRE was identified as a uniporter subunit absolutely required for Ca(2+) 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 Ca(2+) landscape.
Department of Biochemistry, Brandeis University, Waltham, United States.|Howard Hughes Medical Institute, Brandeis University, Waltham, United States.
Ming-Feng
MF
Tsai
Department of Biochemistry, Brandeis University, Waltham, United States.|Howard Hughes Medical Institute, Brandeis University, Waltham, United States.
Charles B
CB
Phillips
Department of Biochemistry, Brandeis University, Waltham, United States.
Matthew
M
Ranaghan
Department of Biochemistry, Brandeis University, Waltham, United States.|Howard Hughes Medical Institute, Brandeis University, Waltham, United States.
Chen-Wei
CW
Tsai
Department of Biochemistry, Brandeis University, Waltham, United States.|Howard Hughes Medical Institute, Brandeis University, Waltham, United States.
Yujiao
Y
Wu
Department of Biochemistry, Brandeis University, Waltham, United States.|Howard Hughes Medical Institute, Brandeis University, Waltham, United States.
Carole
C
Willliams
Department of Biochemistry, Brandeis University, Waltham, United States.|Howard Hughes Medical Institute, Brandeis University, Waltham, United States.
Christopher
0000-0002-0273-8653
C
Miller
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans
D015220:Calcium Channels; C585180:SMDT1 protein, human; C034703:mitochondrial calcium uniporter; D002118:Calcium
EMRE; MCU; biochemistry; calcium transport; human; ion channel; mitochondria