The ability to respond to external mechanical stimuli is of vital importance for many organisms, from unicellular bacteria to higher eukaryotes, where mechanosensation plays a role in processes from tissue development to touch-sensing. In light of this, cells evolved sophisticated molecular machines that are able to sense and transduce membrane tension into chemical signals at the base of signaling cascades. However, many aspects of this, apparently easy, signal interpretation still escape our current understanding: How do membrane protein structural changes record and finally propel mechanical tension and what is the role of the membrane bilayer? We set out to apply a molecular dynamics simulation stretching protocol to the Piezo1 mechanosensitive ion channel in order to decipher its molecular mechanism in a model membrane environment.
The cover image for the April 20 issue of Biophysical Journal is an artistic rendering of our Piezo1 model simulated under mechanical tension. The snapshots were taken from our molecular dynamics simulations and describe the remarkable adaptation of the Piezo blades, shown as a cartoon, to stretch. The C-terminal extracellular domain (CED), which is shown here as a luminous surface, becomes exposed during our stretching protocol, suggesting its importance in shear-stress sensing.
The image was created by Dario De Vecchis using the software VMD, Inkscape, and UCSF Chimera and is freely inspired by old-fashioned blueprints used widely in technical and mechanical drawing. The Piezo1 protein channel is compressed by a virtual piston inside a virtual isolated chamber to resemble our simulation box, where the pressure is monitored by a virtual gauge. Our cover captures the key aspects of our research, which is to “blueprint” a prototype of what has been hypothesized by the community: the in-plane area expansion, on the upper right, accompanied by the progressive flattening, on the lower right, of the fascinating Piezo triskelion. The Piezo1 structures on the right were intentionally rendered in ambient lighting to mimic a chalk sketch but are indeed simulation snapshots.
This illustration describes how our theoretical study allows connection of the Piezo1 activation mechanism to a precise description of the structural rearrangements under mechanical tension, and possibly reveals foundations of Piezo1 signal interpretation.
For more information, the authors’ websites are:
https://medicinehealth.leeds.ac.uk/medicine/staff/485/dr-antreas-kalli
https://medicinehealth.leeds.ac.uk/medicine/staff/1121/professor-david-j-beech
- Dario De Vecchis, David J. Beech, Antreas C. Kalli