Direct observation of the conformational states of PIEZO1 DOI Creative Commons
Eric M. Mulhall, Anant Gharpure, Rachel Lee

et al.

Nature, Journal Year: 2023, Volume and Issue: 620(7976), P. 1117 - 1125

Published: Aug. 16, 2023

Abstract PIEZOs are mechanosensitive ion channels that convert force into chemoelectric signals 1,2 and have essential roles in diverse physiological settings 3 . In vitro studies proposed PIEZO transduce mechanical through the deformation of extensive blades transmembrane domains emanating from a central ion-conducting pore 4–8 However, little is known about how these interact with their native environment which molecular movements underlie activation. Here we directly observe conformational dynamics individual PIEZO1 molecules cell using nanoscopic fluorescence imaging. Compared previous structural models PIEZO1, show significantly expanded at rest by bending stress exerted plasma membrane. The degree expansion varies dramatically along length blade, where decreased binding strength between subdomains can explain increased flexibility distal blade. Using chemical modulators blade channel activation correlated. Our findings begin to uncover activated environment. More generally, as reliably detect shifts single nanometres populations channels, expect this approach will serve framework for analysis membrane proteins

Language: Английский

Discoveries in structure and physiology of mechanically activated ion channels DOI
Jennifer M. Kefauver, Andrew B. Ward, Ardem Patapoutian

et al.

Nature, Journal Year: 2020, Volume and Issue: 587(7835), P. 567 - 576

Published: Nov. 25, 2020

Language: Английский

Citations

457
Molecular mechanosensors in osteocytes DOI Creative Commons
Lei Qin, Wen Liu, Huiling Cao

et al.

Bone Research, Journal Year: 2020, Volume and Issue: 8(1)

Published: June 8, 2020

Abstract Osteocytes, the most abundant and long-lived cells in bone, are master regulators of bone remodeling. In addition to their functions endocrine regulation calcium phosphate metabolism, osteocytes major responsive force adaptation due mechanical stimulation. Mechanically induced formation adaptation, disuse-induced loss skeletal fragility mediated by osteocytes, which sense local cues respond these both direct indirect ways. The mechanotransduction process is a complex but exquisite regulatory between environment, neighboring cells, different functional mechanosensors individual cells. Over past two decades, great efforts have focused on finding various that transmit extracellular signals into regulate gene expression. osteocyte cytoskeleton, dendritic processes, Integrin-based focal adhesions, connexin-based intercellular junctions, primary cilium, ion channels, matrix reported so far with evidence from vitro studies. This review aims give systematic introduction mechanobiology, provide details mechanosensors, discuss roles mechanosensitive signaling pathways homeostasis.

Language: Английский

Citations

324
A Feedforward Mechanism Mediated by Mechanosensitive Ion Channel PIEZO1 and Tissue Mechanics Promotes Glioma Aggression DOI Creative Commons
Xin Chen, Siyi Wanggou,

Ankur Bodalia

et al.

Neuron, Journal Year: 2018, Volume and Issue: 100(4), P. 799 - 815.e7

Published: Oct. 18, 2018

Language: Английский

Citations

317
The mechanosensitive Piezo1 channel is required for bone formation DOI Creative Commons
Weijia Sun, Shaopeng Chi, Yuheng Li

et al.

eLife, Journal Year: 2019, Volume and Issue: 8

Published: July 10, 2019

Mechanical load of the skeleton system is essential for development, growth, and maintenance bone. However, molecular mechanism by which mechanical stimuli are converted into osteogenesis bone formation remains unclear. Here we report that Piezo1, a bona fide mechanotransducer critical various biological processes, plays role in formation. Knockout Piezo1 osteoblast lineage cells disrupts osteoblasts severely impairs structure strength. Bone loss induced unloading blunted knockout mice. Intriguingly, simulated microgravity treatment reduced function suppressing expression Piezo1. Furthermore, osteoporosis patients show closely correlated with dysfunction. These data collectively suggest functions as key conferring mechanosensitivity to determining mechanical-load-dependent formation, represents novel therapeutic target treating or unloading-induced severe loss.

Language: Английский

Citations

315
Force-induced conformational changes in PIEZO1 DOI
Yi‐Chih Lin, Yusong R. Guo,

Atsushi Miyagi

et al.

Nature, Journal Year: 2019, Volume and Issue: 573(7773), P. 230 - 234

Published: Aug. 21, 2019

Language: Английский

Citations

308
Structure and mechanogating of the mammalian tactile channel PIEZO2 DOI
Li Wang, Heng Zhou, Mingmin Zhang

et al.

Nature, Journal Year: 2019, Volume and Issue: 573(7773), P. 225 - 229

Published: Aug. 21, 2019

Language: Английский

Citations

294
Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation DOI Creative Commons

Keiko Nonomura,

Viktor Lukacs,

Daniel T. Sweet

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(50), P. 12817 - 12822

Published: Nov. 27, 2018

Significance PIEZOs are mechanically activated cation channels. Recently, loss-of-function mutations of human PIEZO1 were found among patients with familial lymphedema, suggesting a requirement in the lymphatic system. In this paper, utilizing mouse models lacking endothelial cells, we show that ion channel is required for formation valves, key structure proper circulation lymph body. The valve provides mechanistic insight on how variants cause dysfunction patients. This study also extends relevance beyond acute signaling molecules (e.g., touch sensation) and highlights importance these channels controlling morphological/structural specification during development.

Language: Английский

Citations

227
Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis DOI Creative Commons
Justin T. Marinko, Hui Huang, Wesley D. Penn

et al.

Chemical Reviews, Journal Year: 2019, Volume and Issue: 119(9), P. 5537 - 5606

Published: Jan. 4, 2019

Advances over the past 25 years have revealed much about how structural properties of membranes and associated proteins are linked to thermodynamics kinetics membrane protein (MP) folding. At same time biochemical progress has outlined cellular proteostasis networks mediate MP folding manage misfolding in cell. When combined with results from genomic sequencing, these studies established paradigms for molecular etiologies a variety diseases. This emerging framework paved way development new class small molecule “pharmacological chaperones” that bind stabilize misfolded variants, some which now clinical use. In this review, we comprehensively outline current perspectives on integral MPs as well mechanisms quality control. Based perspectives, highlight opportunities innovations bridge our understanding energetics nuanced complexity biological systems. Given many linkages between human disease, also examine exciting leverage advances address challenges therapeutics precision medicine.

Language: Английский

Citations

226
A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel DOI Creative Commons
Yanfeng Wang, Shaopeng Chi,

Huifang Guo

et al.

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: April 3, 2018

Abstract Piezo1 represents a prototype of eukaryotic mechanotransduction channels. The full-length 2547-residue mouse possesses unique 38-transmembrane-helix (TM) topology and is organized into three-bladed, propeller-shaped architecture, comprising central ion-conducting pore, three peripheral blade-like structures, 90-Å-long intracellular beam-resembling structures that bridge the blades to pore. However, how mechanical force chemicals activate gigantic machinery remains elusive. Here we identify novel set chemical activators, termed Jedi, which activates through extracellular side blade instead C-terminal domain indicating long-range allosteric gating. Remarkably, Jedi-induced activation requires key components, including two loops in distal leucine residues proximal end beam. Thus, employs blade-beam-constituted lever-like apparatus as designated transduction pathway for long-distance mechano- chemical-gating

Language: Английский

Citations

212
Dietary fatty acids fine-tune Piezo1 mechanical response DOI Creative Commons
Luis O. Romero, Andrew E. Massey, Alejandro Mata-Daboin

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: March 13, 2019

Mechanosensitive ion channels rely on membrane composition to transduce physical stimuli into electrical signals. The Piezo1 channel mediates mechanoelectrical transduction and regulates crucial physiological processes, including vascular architecture remodeling, cell migration, erythrocyte volume. identity of the components that modulate function remain largely unknown. Using lipid profiling analyses, we here identify dietary fatty acids tune mechanical response. We find margaric acid, a saturated acid present in dairy products fish, inhibits activation polyunsaturated (PUFAs), fish oils, inactivation. Force measurements reveal increases bending stiffness, whereas PUFAs decrease it. use supplementation abrogate phenotype gain-of-function mutations causing human dehydrated hereditary stomatocytosis. Beyond Piezo1, our findings demonstrate cell-intrinsic profile changes metabolism can dictate cell's response cues.

Language: Английский

Citations

211