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

Affiliation

Chong J(1), De Vecchis D(1), Hyman AJ(1), Povstyan OV(1), Ludlow MJ(1), Shi J(1), Beech DJ(2), Kalli AC(3).
Author information:
(1)Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom.
(2)Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom. Electronic address: [Email]
(3)Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom. Electronic address: [Email]

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 (PIP2) molecules, and 3) cholesterol changes the depth of the dome and PIP2 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 PIP2 interactions.