Architecture of the mammalian mechanosensitive Piezo1 channel

Abstract

Piezo proteins are evolutionarily conserved and functionally diverse mechanosensitive cation channels. However, the overall structural architecture and gating mechanisms of Piezo channels have remained unknown. Here we determine the cryo-electron microscopy structure of the full-length (2,547 amino acids) mouse Piezo1 (Piezo1) at a resolution of 4.8 Å. Piezo1 forms a trimeric propeller-like structure (about 900 kilodalton), with the extracellular domains resembling three distal blades and a central cap. The transmembrane region has 14 apparently resolved segments per subunit. These segments form three peripheral wings and a central pore module that encloses a potential ion-conducting pore. The rather flexible extracellular blade domains are connected to the central intracellular domain by three long beam-like structures. This trimeric architecture suggests that Piezo1 may use its peripheral regions as force sensors to gate the central ion-conducting pore.

New insights on hereditary erythrocyte membrane defects

“…This protein has been identified in the RBC membrane, and in mice it has been shown to form a tetramer of about 1.2 million daltons; it is therefore the largest ion channel identified to date, and moreover it regulates mechanotransductive release of ATP from human RBCs. [40][41][42][43] The identified mutations are missense and mainly located in the highly conserved C-terminus of the protein, recently described to form the pore of the channel. 44 Several electrophysiology studies demonstrated that the mutations cause a gain-of-function phenotype with delayed inactivation of the channel, 38,39,45 sugUpdate of the red cell membrane disorders haematologica | 2016; 101 (11)gesting increased cation permeability leads to DHS erythrocyte dehydration.…”

Demystifying Mechanosensitive Piezo Ion Channels

“…For instance, the peripheral regions may function as force sensors and transducers to gate the central pore. In line with this idea, comparing the different classes of cryo-EM structures of Piezo1 reveals that the peripheral regions, particularly the 'blade' domains, are highly flexible [6].…”

“…They first reported in Nature a cryo-electron microscopy (cryo-EM) structure of the full-length mouse Piezo1 protein (2547 residues per monomer), revealing its overall architecture and distinct domains [6]. In another study published recently in Neuron, on the basis of the Piezo1 structure they carried out a comprehensive structure-guided functional analysis, leading to the identification of the ion-conducting pore and key pore determinants, as well as mechanotransduction components, which define the ion-conducting properties and gating by mechanical stimuli, respectively [7].…”

“…In the first study, by taking advantage of the recent advances in cryo-EM techniques, and in combination with their expertise in protein engineering, expression, and purification in mammalian expression systems, Ge et al [6] successfully determined a medium-resolution cryo-EM structure of the Piezo1 channel. Strikingly, the Piezo1 protein assembles as a *0.9 megaDalton trimeric threebladed, propeller-like architecture comprising a central pore module and three extended peripheral wings (Fig.…”

“…On the basis of the Piezo1 structure, the pore module has been tentatively assigned to the C-terminal region (residues 2189-2547) containing the last two transmembrane segments (Fig. 1B) [6]. To functionally validate this assignment, Zhao et al took advantage of the distinct pore properties of mouse and fly Piezos.…”