Structural conservation and ion selectivity adaptation of the mechanically activated PIEZO channel

PIEZO proteins form evolutionarily conserved mechanically activated ion channels, and the prototype mouse PIEZO1 (mPIEZO1) is cation selective. However, the evolutionary conservation and adaptation of the structure-function properties of PIEZOs remain poorly understood. Here, we discover that Drosophila PIEZO (dPIEZO) exhibits unusual ion selectivity for both Cl^- and Ca²⁺. Its cryoelectron microscopy (cryo-EM) structure adopts the characteristic three-bladed, propeller-shaped architecture of mPIEZO1 but in a distinct conformational state. We identify that the lateral-plug domain (Arg1385-Ala1397) and key residues, such as His1391 and Arg1396, determine the distinct ion selectivity of dPIEZO. His1391 is evolutionarily conserved from insects to mammals and mediates pH-dependent tuning of the ion selectivity of dPIEZO. Evolving Arg1396 to His in mammalian PIEZO1 might functionally change the lateral-plug domain from a selectivity filter to a pluggable gate. Together, these findings shed light on the evolutionary conservation, adaptation, and regulation of the structure-function properties of PIEZO channels.