Piezo1 Decodes Mechanical Forces via Allosteric Network Reprogramming

TL;DR

This study uncovers how Piezo1 ion channels decode different mechanical stimuli through distinct, dynamically reconfigurable allosteric pathways, advancing understanding of mechanotransduction at the molecular level.

Contribution

It reveals that Piezo1 employs different allosteric pathways depending on the type of mechanical force, demonstrating dynamic reprogramming of its signaling network.

Findings

Tangent tension activates a lever-like linear pathway.

Shockwave induces a two-stage gating mechanism.

Allosteric network reconfiguration depends on stimulus type.

Abstract

Understanding how molecular machines transduce mechanical force into chemical signals is a central goal in chemistry. The mechanosensitive ion channel Piezo1 is an archetypal nanoscale mechanotransducer, but the molecular principles by which it decodes distinct mechanical stimuli remain elusive. Here, we combine large-scale molecular dynamics simulations with time-series causal inference to elucidate the dynamic allosteric communication networks within Piezo1 under both quasi-static membrane tension and shockwave-induced cavitation. Under tangential tension, Piezo1 employs the lever-like pathway, a linear, feed-forward pathway propagating the signal from peripheral mechanophores to the central pore. In contrast, a shockwave impulse in the normal direction triggers a two-stage gating mechanism based on the dynamic reprogramming of the allosteric network. An initial compression phase activates an apical shortcut pathway originating from the cap domain. A subsequent tension phase utilizes a rewired network with complex feedback loops to drive the channel to a fully open state. These findings reveal that the allosteric wiring of a molecular machine is not static but can be dynamically reconfigured by the nature of the physical input. This principle of force-dependent pathway selection offers a new framework for understanding mechanochemistry and for designing programmable, stimuli-responsive molecular systems.