8ixo
Intermediate structure of mPIEZO1-S2472E
Structural highlights
FunctionPIEZ1_MOUSE Pore-forming subunit of a mechanosensitive non-specific cation channel. Generates currents characterized by a linear current-voltage relationship that are sensitive to ruthenium red and gadolinium. Plays a key role in epithelial cell adhesion by maintaining integrin activation through R-Ras recruitment to the ER, most probably in its activated state, and subsequent stimulation of calpain signaling. In the kidney, may contribute to the detection of intraluminal pressure changes and to urine flow sensing. Acts as shear-stress sensor that promotes endothelial cell organization and alignment in the direction of blood flow through calpain activation. Plays a key role in blood vessel formation and vascular structure in both development and adult physiology.[1] [2] [3] [4] [5] Publication Abstract from PubMedPIEZO1 is a mechanically activated cation channel that undergoes force-induced activation and inactivation. However, its distinct structural states remain undefined. Here, we employed an open-prone PIEZO1-S2472E mutant to capture an intermediate open structure. Compared with the curved and flattened structures of PIEZO1, the S2472E-Intermediate structure displays partially flattened blades, a downward and rotational motion of the top cap, and a spring-like compression of the linker connecting the cap to the pore-lining inner helix. These conformational changes open the cap gate and the hydrophobic transmembrane gate, whereas the intracellular lateral plug gate remains closed. The flattened structure of PIEZO1 with an up-state cap and closed cap gate might represent an inactivated state. Molecular dynamics (MD) simulations of ion conduction support the closed, intermediate open, and inactivated structural states. Mutagenesis and electrophysiological studies identified key domains and residues critical for the mechanical activation of PIEZO1. These studies collectively define the distinct structural states and gating transitions of PIEZO1. An intermediate open structure reveals the gating transition of the mechanically activated PIEZO1 channel.,Liu S, Yang X, Chen X, Zhang X, Jiang J, Yuan J, Liu W, Wang L, Zhou H, Wu K, Tian B, Li X, Xiao B Neuron. 2024 Dec 19:S0896-6273(24)00877-8. doi: 10.1016/j.neuron.2024.11.020. PMID:39719701[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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