Structure of the MICU1-MICU2 heterodimer provides insights into the gatekeeping threshold shift

IUCrJ
Jongseo ParkSoo Hyun Eom

Abstract

Mitochondrial calcium uptake proteins 1 and 2 (MICU1 and MICU2) mediate mitochondrial Ca2+ influx via the mitochondrial calcium uniporter (MCU). Its molecular action for Ca2+ uptake is tightly controlled by the MICU1-MICU2 heterodimer, which comprises Ca2+ sensing proteins which act as gatekeepers at low [Ca2+] or facilitators at high [Ca2+]. However, the mechanism underlying the regulation of the Ca2+ gatekeeping threshold for mitochondrial Ca2+ 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 me-thio-nine knobs stabilizing the heterodimer in an apo state. Structural analysis suggests how the heterodimer sets a higher Ca2+ 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.

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Citations

Jul 16, 2020·ELife·Chongyuan WangStephen Barstow Long
May 28, 2020·International Journal of Molecular Sciences·Megan NoblePeter B Stathopulos
Dec 10, 2020·American Journal of Physiology. Cell Physiology·B Rita AlevriadouMuniswamy Madesh
May 12, 2020·Journal of Molecular and Cellular Cardiology·Julia C Liu
Oct 27, 2021·Physiological Reviews·Joanne F Garbincius, John W Elrod

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Methods Mentioned

BETA
size-exclusion chromatography
X-ray

Software Mentioned

PRODIGY
POINTLESS
AIMLESS
Coot
phenix
Buccaneer
CCP
SHELXE
PDBePISA
SHELXD

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