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Author(s): Lee, Youngjin; Kim, JiHun; Lee, Bora; Kang, Jung Youn; Lim, Jia Jia; Youn, Hyung-Seop; Lee, Jung-Gyu; An, Jun Yop; Park, Kyoung Ryoung; Kim, Tae Gyun; Kim, Do Han; Eom, Soo Hyun

Abstract: Mitochondrial calcium (Ca2+) homeostasis is essential for cell survival and death. The mitochondrial calcium uniporter (MCU) homo-tetramer is a selective Ca2+ channel responsible for mitochondrial Ca2+ uptake. Its paralog, MCUb, can form a Ca2+-impermeable hetero-tetramer with MCU exerting a dominant-negative function. We report the structural modeling for MCUb N-terminal domain (NTD), which showed 83% sequence homology with MCU NTD. The MCUb NTD model structure forms a stable globular domain via a hydrophobic interior and contains conserved putative phosphorylation and ubiquitination sites. The MCUb NTD structure is similar to that of MCU NTD with a root mean square deviation (RMSD) of 0.3 Å for 96 Cα atoms. The MCUb NTD forms a stable heterodimer with MCU NTD mainly by electrostatic interaction, although both NTDs are stable as monomers. Besides, our cross-linking results reveal that both NTDs form high-order oligomers. Our findings suggest that stable heterodimer formation of MCU-MCUb NTDs affects MCU NTD clustering, resulting in inefficient clustering of MCU for efficient Ca2+ permeation at the high [Ca2+] microdomain.

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