Nickolls et al. identify a clinical variant in PIEZO2 that impairs touch sensation and body awareness. By showing how this variant prevents PIEZO channels from opening and deforming under pressure, the study adds to our understanding of how specific PIEZO protein domains contribute to force-induced conformational changes.

PIEZO2 is intrinsically more rigid than PIEZO1, and disparate mechanical stimuli paradoxically evoke opposite conformational and gating responses in each channel.