Cryo-EM structure of TMEM63C suggests it functions as a monomer

The TMEM63 family proteins (A, B, and C), calcium-permeable channels in animals that are preferentially activated by hypo-osmolality, have been implicated in various physiological functions. Deficiency of these channels would cause many diseases including hearing loss. However, their structures and physiological roles are not yet well understood. In this study, we determined the cryo-EM structure of the mouse TMEM63C at 3.56 Å, and revealed structural differences compared to its plant orthologues OSCAs. Further structural guided mutagenesis and electrophysiological studies demonstrated the important roles of the coupling of TM0 and TM6 in channel activity. Additionally, we confirmed that the physiological state of TMEM63C is monomer, while TMEM63B is a mix of monomer and dimer in cells, suggesting that oligomerization is a novel regulatory mechanism for TMEM63 proteins.