Significance Aristotle’s five senses—sight, smell, taste, hearing, and touch—are crucial for the perception of and interaction with the environment. While the molecular machineries that detect visual, olfactory, gustatory, and auditory stimuli are well characterized, comparatively little is known about how the sense of touch works at the molecular level. Here we identified and characterized intraprotein domain interfaces that govern the mechanosensitivity of the ion channel PIEZO2. Considering that PIEZO2 is an important detector of tactile and painful mechanical stimuli, selectively blocking these domain interactions in primary afferent neurons might provide an effective means to modulate pain sensitivity. Thus our work provides the basis for the development of additional types of analgesics that attack pain at its source.