Structure of the MICU1–MICU2 heterodimer provides insights into the gatekeeping threshold shift
Jongseo Park, Youngjin Lee, Taein Park, Jung Youn Kang, Sang A. Mun, Minwoo Jin, Jihyeong Yang, Soo Hyun Eom
Abstract
Mitochondrial calcium uptake proteins 1 and 2 (MICU1 and MICU2) mediate mitochondrial Ca 2+ influx via the mitochondrial calcium uniporter (MCU). Its molecular action for Ca 2+ uptake is tightly controlled by the MICU1–MICU2 heterodimer, which comprises Ca 2+ sensing proteins which act as gatekeepers at low [Ca 2+ ] or facilitators at high [Ca 2+ ]. However, the mechanism underlying the regulation of the Ca 2+ gatekeeping threshold for mitochondrial Ca 2+ uptake through the MCU by the MICU1–MICU2 heterodimer remains unclear. In this study, we determined the crystal structure of the apo form of the human MICU1–MICU2 heterodimer that functions as the MCU gatekeeper. MICU1 and MICU2 assemble in the face-to-face heterodimer with salt bridges and methionine knobs stabilizing the heterodimer in an apo state. Structural analysis suggests how the heterodimer sets a higher Ca 2+ threshold than the MICU1 homodimer. The structure of the heterodimer in the apo state provides a framework for understanding the gatekeeping role of the MICU1–MICU2 heterodimer.