Modeling of full-length Piezo1 suggests importance of the proximal N-terminus for dome structure

Abstract

Piezo1 forms a mechanically activated calcium-permeable nonselective cation channel that is functionally important in many cell types. Structural data exist for C-terminal regions, but we lack information about N-terminal regions and how the entire channel interacts with the lipid bilayer. Here, we use computational approaches to predict the three-dimensional structure of the full-length Piezo1 and simulate it in an asymmetric membrane. A number of novel insights are suggested by the model: 1) Piezo1 creates a trilobed dome in the membrane that extends beyond the radius of the protein, 2) Piezo1 changes the lipid environment in its vicinity via preferential interactions with cholesterol and phosphatidylinositol 4,5-bisphosphate (PIP 2 ) molecules, and 3) cholesterol changes the depth of the dome and PIP 2 binding preference. In vitro alteration of cholesterol concentration inhibits Piezo1 activity in a manner complementing some of our computational findings. The data suggest the importance of N-terminal regions of Piezo1 for dome structure and membrane cholesterol and PIP 2 interactions.

Piezo1 and Piezo2 foster mechanical gating of K2P channels

“…High speed atomic force microscopy (AFM) imaging elegantly demonstrated that Piezo1 reversibly flattens, with blades moving down, when force is applied to the channel (Lin et al, 2019). Recent molecular dynamics simulation studies also indicate that Piezo1 changes the lipid environment in its vicinity through numerous preferential interactions with various lipids, including cholesterol (Buyan et al, 2020;Chong et al, 2021).…”

Channelling the Force to Reprogram the Matrix: Mechanosensitive Ion Channels in Cardiac Fibroblasts

“…Piezo1 has a curved structure, creating a dome shape in the membrane [204] which extends beyond the radius of Piezo1 [208]. Flattening of the dome shape, via mechanical tension, has been hypothesised to provide the energy requirement for mechanical activation of the channel [208]. Piezo1 responds to a number of different types of mechanical stimuli in tissue culture, including lateral membrane tension [79,202,209], compression [210,211], osmotic swelling [212], and rhythmic mechanical stimulus [213], including 24-h cyclic stretch [214].…”

“…The Piezo1 channel comprises three Piezo1 proteins arranged to form a trimer, or triskelion shape [ 202 , 203 , 204 , 205 , 206 ], with three propeller blade-like structures projecting outward from a central pore, formed at the C-terminus of each protein [ 207 ]. The central pore constitutes the non-selective cation channel [ 207 ], with an alpha helix beam connecting each propeller-like blade structure to the central pore [ 203 , 208 ]. Piezo1 has a curved structure, creating a dome shape in the membrane [ 204 ] which extends beyond the radius of Piezo1 [ 208 ].…”

“…The central pore constitutes the non-selective cation channel [ 207 ], with an alpha helix beam connecting each propeller-like blade structure to the central pore [ 203 , 208 ]. Piezo1 has a curved structure, creating a dome shape in the membrane [ 204 ] which extends beyond the radius of Piezo1 [ 208 ]. Flattening of the dome shape, via mechanical tension, has been hypothesised to provide the energy requirement for mechanical activation of the channel [ 208 ].…”

“…Piezo1 has a curved structure, creating a dome shape in the membrane [ 204 ] which extends beyond the radius of Piezo1 [ 208 ]. Flattening of the dome shape, via mechanical tension, has been hypothesised to provide the energy requirement for mechanical activation of the channel [ 208 ].…”