Journal:IUCrJ:S2052252520001840

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 and Soo Hyun Eom ^[1]

Molecular Tour
Mitochondrial calcium homeostasis plays essential roles in modulating various cellular functions, and tightly controlled by several Ca²⁺ channels, especially mitochondrial calcium uniporter (MCU) complex. Open or close of MCU channel is regulated by mitochondrial calcium uptakes (MICU1, MICU2 and MICU3). MICUs have Ca²⁺ binding EF-hand motifs, which form homo- or hetero-oligomers, and functions as gatekeepers in the Ca²⁺-free (apo) state and facilitators in the Ca2+-bound state. Blocking or activation of mitochondrial Ca²⁺ (Ca²⁺_m) uptake by the MCU complex is affected by Ca²⁺ binding to the MICUs participating in the MCU complex because a strong correlation between Ca²⁺ binding affinity and the MCU Ca²⁺ gatekeeping threshold for Ca²⁺_m uptake has been demonstrated. Generally, MICU1 and MICU2 assemble as a heterodimer in most tissues, but mechanism underlying the regulation of Ca2+ uptake by the heterodimer through MCU is unclear.

The crystal structure of an apo human MICU1-MICU2 heterodimer was presented. The heterodimer had an asymmetric interface:

• Interface 1
• Interface 2.

Interestingly, the rigid interface 1 included a D231(MICU1)-R352(MICU2) salt bridge, and D231 is a highly conserved residue for Ca²⁺ coordination in MICU1 EF-hand 1. Thus, MICU1 EF-hand 1 can bind calcium when the salt bridge dissociates. The tight interaction in apo state of MICU1-MICU2 might hinder the conformational changes required for the Ca²⁺ binding, resulting in a lower Ca²⁺ binding affinity in the MICU1-MICU2 heterodimer as compared to that of MICU1 homodimer.

PDB reference: crystal structure of the mitochondrial calcium uptake 1 and 2 heterodimer (MICU1–MICU2 heterodimer) in an apo state, 6le5.

References

1. ↑ Park J, Lee Y, Park T, Kang JY, Mun SA, Jin M, Yang J, Eom SH. Structure of the MICU1-MICU2 heterodimer provides insights into the gatekeeping threshold shift. IUCrJ. 2020 Feb 27;7(Pt 2):355-365. doi: 10.1107/S2052252520001840. eCollection, 2020 Mar 1. PMID:32148862 doi:http://dx.doi.org/10.1107/S2052252520001840