Structural Bases for Chemical and Mechanical Gating in the Piezo1 Channel

Abstract

Mechanosensitive Piezo channels possess a propeller-like structure with a central cation-selective pore and three putative force-sensing blades encompassing several helical bundles called Piezo repeats. How membrane stretch and chemical agonists modulate Piezo channels is unknown. Here, using all-atom molecular dynamic stimulations and experimental assays, we localize the binding site of Yoda1, a small molecule Piezo1 activator, and identify stretch-induced conformational rearrangements of the blades. Yoda1 binding uncouples two adjacent Piezo repeats, facilitating stretch-induced blade motions, and alters long-range residue-residue contacts between pore and blades, as evidenced by Yoda1-induced channel activation of a mechanically-insensitive mutant. In addition, cation-selective fenestrations allow potassium, not chloride, ions to enter a pore vestibule. Our work reveals the structural bases of cationic selectivity, chemical modulation and mechanical sensing in a mammalian Piezo channel.