The crystal structure of MICU2 provides insight into Ca2+ binding and MICU1-MICU2 heterodimer formation.
The mitochondrial calcium uniporter (MCU) complex mediates the uptake of Ca2+ into mitochondria. Its activity is regulated by a heterodimer of MICU1 and MICU2, two EF-hand-containing proteins that act as the main gatekeeper of the uniporter. Herein we report the crystal structure of human MICU2 at 1.96 Å resolution. Our structure reveals a dimeric architecture of MICU2, in which each monomer adopts the canonical two-lobe structure with a pair of EF-hands in each lobe. Both Ca2+ -bound and Ca2+ -free EF-hands are observed in our structure. Moreover, we characterize the interaction sites within the MICU2 homodimer, as well as the MICU1-MICU2 heterodimer in both Ca2+ -free and Ca2+ -bound conditions. Glu242 in MICU1 and Arg352 in MICU2 are crucial for apo heterodimer formation, while Phe383 in MICU1 and Glu196 in MICU2 significantly contribute to the interaction in the Ca2+ -bound state. Based on our structural and biochemical analyses, we propose a model for MICU1-MICU2 heterodimer formation and its conformational transition from apo to a more compact Ca2+ -bound state, which expands our understanding of this co-regulatory mechanism critical for MCU's mitochondrial calcium uptake function.
['Wu|Wenping|W|0000-0002-4905-6705', 'Shen|Qingya|Q|0000-0001-6602-7116', 'Lei|Zhen|Z|', 'Qiu|Zhiyu|Z|', 'Li|Dan|D|', 'Pei|Hairun|H|', 'Zheng|Jimin|J|0000-0001-6242-152X', 'Jia|Zongchao|Z|0000-0002-9322-9394']
D002118:Calcium D015220:Calcium Channels D002135:Calcium-Binding Proteins D027682:Cation Transport Proteins D019281:Dimerization D006801:Humans D033681:Mitochondrial Membrane Transport Proteins D008954:Models, Biological D011485:Protein Binding
MICU2 mitochondrial calcium uniporter EF-hands MICU1-MICU2 complex