Piezo1 footprint nanoarchitecture: from individual channels to collective behaviour and from outward to inward curvature

Abstract

Piezo1 acts as a key architect of the cell membrane, generating a curved nanodome that extends beyond the protein trimer itself. Although Piezo1 intrinsically favours an outward (convex) membrane footprint, recent high-resolution studies have revealed that clustered channels can reorganize into inward (concave), pit-shaped membrane invaginations. This review synthesizes these findings and addresses the apparent contradiction between reports of suppressed and enhanced mechanosensitivity in Piezo1 clusters. We propose a unifying framework in which the outward-to-inward transition is governed by the geometrical regularity of membrane curvature, particularly within curvature fields associated with focal adhesions. Regions with highly variable curvature act as mechanical noise buffers, disrupting long-range elastic coupling and preserving outward Piezo1 footprints. In contrast, regular curvature fields promote coherent interactions between neighbouring channels, facilitating collective deformation and increasing the likelihood of curvature inversion. Cholesterol provides an additional regulatory mechanism by stabilizing outward Piezo1 conformations through lipid–protein interactions and increased membrane stiffness. We introduce the concept of sign-switching susceptibility, suggesting that Piezo1 collective behaviour depends not only on channel density but also on focal adhesion architecture and curvature coherence. Together, geometrical disorder and lipid-mediated stabilization may enable cells to tune mechanosensitivity in dynamically remodelling environments.