FIGURE 1.

Functional architecture of the MCU_cx based on structural studies. (A) Electrostatic interactions between the channel pore and MICU1 (red arrow) block the MCU complex when Ca²⁺ levels are low. (B) Elevated Ca²⁺ levels increase Ca²⁺ binding to MICU1/MICU2 heterodimers that exposes positively charged amino acids in MICU1. This strengthens the association of MICU1 with negatively charged amino acids in EMRE which displaces the MICU1/2 dimer from the channel pore (white arrow) resulting in increased Ca²⁺ influx into the matrix (green arrow). Based on recent cryo-EM studies and size on native gels (∼480 kD), it is likely that the MCU_cx holocomplex consists of two conjoined dimers of the MCU/EMRE pore which are each associated with a single MICU1/MICU2 heterodimer. (See section “2.1. Architecture of the MCUcx” for abbreviations and mechanistic details).