A mechanism for the activation of the mechanosensitive Piezo1 channel by the small molecule Yoda1

Wesley M Botello-Smith,Jérôme J Lacroix,Yun Luo,Yi-Chun Lin,Han Zhang,Wenjuan Jiang,Alper D Ozkan,Christine N Pham

doi:10.1038/s41467-019-12501-1

Wesley M Botello-Smith, Jérôme J Lacroix + Show 6 more

Open Access

https://doi.org/10.1038/s41467-019-12501-1

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Journal: Nature Communications	Publication Date: Oct 3, 2019
Citations: 146	License type: open-access

Affiliation: Western University of Health Sciences

Abstract

Mechanosensitive Piezo1 and Piezo2 channels transduce various forms of mechanical forces into cellular signals that play vital roles in many important biological processes in vertebrate organisms. Besides mechanical forces, Piezo1 is selectively activated by micromolar concentrations of the small molecule Yoda1 through an unknown mechanism. Here, using a combination of all-atom molecular dynamics simulations, calcium imaging and electrophysiology, we identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain, approximately 40 Å away from the central pore. Our simulations further indicate that the presence of the agonist correlates with increased tension-induced motions of the Yoda1-bound subunit. Our results suggest a model wherein Yoda1 acts as a molecular wedge, facilitating force-induced conformational changes, effectively lowering the channel’s mechanical threshold for activation. The identification of an allosteric agonist binding site in Piezo1 channels will pave the way for the rational design of future Piezo modulators with clinical value.

Highlights

Mechanosensitive Piezo[1] and Piezo[2] channels transduce various forms of mechanical forces into cellular signals that play vital roles in many important biological processes in vertebrate organisms
Abnormal Piezo channel activity caused by inherited mutations, genetic manipulation or physiological regulation has been linked to a variety of pathological conditions such as xerocytosis, lymphedema, arthrogryposis, abnormal vascular development, sleep apnea, allodynia and the loss of proprioception[10,11,12,13,14,15,16,17,18,19,20]
Recent advances in cryo-electron microscopy have enabled the capture of mouse Piezo[1] in non-conducting states, which presumably correspond to the canonical closed conformation populated in absence of external mechanical force[25,26,27]

Summary

Introduction

Mechanosensitive Piezo[1] and Piezo[2] channels transduce various forms of mechanical forces into cellular signals that play vital roles in many important biological processes in vertebrate organisms. Recent advances in cryo-electron microscopy (cryo-EM) have enabled the capture of mouse Piezo[1] (mPZ1) in non-conducting states, which presumably correspond to the canonical closed conformation populated in absence of external mechanical force[25,26,27] These structures reveal a propeller-like structure with a central pore surrounded by three large peripheral domains called arms, or blades. The Yoda[1] binding site(s) could be identified by solving the structure of a Yoda1Piezo[1] complex, the resolution of current cryo-EM structures (3.5 to 4 Å) may be too low for unambiguous identification of the small, 29-atoms Yoda[1] molecule To identify this binding site, we perform microseconds-long all-atom molecular dynamics (MD) simulations of mPZ1 in the presence of multiple Yoda[1] ligands and in absence or presence of membrane stretch. We report the identification of an allosteric Yoda[1] binding site and propose a simple mechanism by which Yoda[1] may promote Piezo[1] opening in the presence of membrane stretch

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