Chemical Gating of the Mechanosensitive Piezo1 Channel by Asymmetric Binding of its Agonist Yoda1

Abstract

Piezo proteins are homotrimeric ion channels that play major roles in normal and pathological mechanotransduction signaling in mammalian organisms. Their pharmacological control hence represents a potential therapeutic avenue. Yoda1, a Piezo1-selective small molecule agonist, is the only known selective Piezo modulator. How Yoda1 selectively interacts with Piezo1 and opens its pore is unknown. Here, by engineering and characterizing chimeras, we identified a minimal region responsible for Yoda1 binding. This region is located at the interface between the pore and the putative mechanosensory domains in each subunit. By characterizing hybrid channels containing Yoda1-insensitive and Yoda1-sensitive monomers, we demonstrate that the presence of only one Yoda1-sensitive Piezo1 subunit is sufficient for chemical activation, implicating that the asymmetric binding of Yoda1 to a single subunit enables channel opening. These findings shed light onto the gating mechanisms of Piezo channels and will pave the way for the rationale design of new Piezo channels modulators.