Computational studies of Piezo1 yield insights into key lipid-protein interactions, channel activation, and agonist binding

Abstract

Piezo1 is a mechanically gated ion channel responsible for converting mechanical stimuli into electrical signals in mammals, playing critical roles in vascular development and blood pressure regulation. Dysfunction of Piezo1 has been linked to several disorders, including hereditary xerocytosis (gain-of-function) and generalised lymphatic dysplasia (loss-of-function), as well as a common polymorphism associated with protection against severe malaria. Despite the important physiological roles played by Piezo1, its recent discovery means that many aspects underlying its function are areas of active research. The recently elucidated cryo-EM structures of Piezo1 have paved the way for computational studies, specifically molecular dynamic simulations, to examine the protein's behaviour at an atomistic level. These studies provide valuable insights to Piezo1's interactions with surrounding membrane lipids, a small-molecule agonist named Yoda1, and Piezo1's activation mechanisms. In this review, we summarise and discuss recent papers which use computational techniques in combination with experimental approaches such as electrophysiology/mutagenesis studies to investigate Piezo1. We also discuss how to mitigate some shortcomings associated with using computational techniques to study Piezo1 and outline potential avenues of future research.

Keywords: Channel activation; Computational techniques; Piezo1.

Fig. 1

Piezo1–lipid interactions and curvature of the membrane. A A top and side view of Piezo1’s structure. Each monomer is coloured differently. B Schematic of Piezo1, with the unresolved regions in grey and each transmembrane helix unit (THU) in a different colour. Cholesterol interaction sites are yellow boxes, while PIP2 sites are purple boxes. The dark grey box in the background is the membrane. C Density plots of cholesterol (left) and PIP2 (right) around Piezo1 (D) PIP binding sites highlighted on one monomer (left), with a key PIP binding site corresponding to a Delta4K mutation (inset). E Cholesterol binding site corresponding to a site identified by experimental crosslinking. F Lipid depletion/enrichment indices highlighting which lipids are more likely to be present closer to Piezo1. G Curvature of the membrane induced by Piezo1. A, C, and G are adapted from Chong et al. (2021). B, D, E, and F are adapted from Buyan et al. (2020)

Fig. 2

Mechanical activation of Piezo1 in MD simulations: A crowding-induced opening — representative structures of Piezo1 in the closed (0 us, red) and open (2 us, blue) state (B). Membrane tension-induced opening — Piezo1 in the closed (0 ns, left) and open state (50 ns, right). A is De Vecchis et al. (2021) adapted from Jiang et al. (2021) under the Creative Commons Attribution 4.0 International Licence. B is adapted from under the Creative Commons Attribution 4.0 International Licence

Fig. 3

Small molecules and Piezo1: A chemical structures of the 4 small-molecule modulators of Piezo1: Yoda1, Dooku1, Jedi1, and Jedi2. B Yoda1 in its putative binding site, between THU 8 and 9. C A sequence alignment (T-Coffee) of the mouse Piezo1 (UniProt ID: E2JF22) and mouse Piezo2 genes (UniProt ID: Q8CD54), showing the three Piezo1 residues (A1718, A2091, and A2094) which coordinate Yoda1 binding in Botello-Smith et al. (2019), are conserved/similar in Piezo2. B is adapted from Botello-Smith et al. (2019) under the Creative Commons Attribution 4.0 International Licence