Force-induced conformational changes in PIEZO1

Lin, Yi-Chih; Guo, Yusong R.; Miyagi, Atsushi; Levring, Jesper; MacKinnon, Roderick; Scheuring, Simon

doi:10.1038/s41586-019-1499-2

Cited by 235 publications

(247 citation statements)

References 45 publications

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“…shows that the overall structures are very similar (Supplementary Figure 1E). The N-terminal 350 region of the blades of the Piezo2 structure is more elevated relative to our Piezo1full structure 351 (Supplementary Figure 1F), however the Piezo1 blades are highly flexible in response to force 352 (Lin et al, 2019), and the same is likely to be true of Piezo2. Therefore, differences between 353 these static structures may not represent dynamic differences in vivo.…”

mentioning

confidence: 77%

“…This observation suggests that Piezo1 may be not only a 375 passive receptor of mechanical forces but could transmit physical effects at long range through 376 the membrane. This idea of Piezo1 applying force to the membrane while the membrane 377 applies force to the protein is supported by recent work from the MacKinnon and Scheuring 378 groups (Lin et al, 2019). The topology may also amplify Piezo1 tension sensitivity as 379 previously suggested (Guo and MacKinnon, 2017).…”

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confidence: 84%

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Computational reconstruction of the complete Piezo1 structure reveals a unique footprint and specific lipid interactions

Chong

Vecchis

Hyman

et al. 2019

Preprint

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14 Piezo1 is a critical mechanical sensor in many cells. It is activated by mechanical force thus 15 allowing cells to sense the physical environment and respond to stress. Structural data have 16suggested that Piezo1 has a curved shape. Here, we use computational approaches to model, 17for the first time, the 3D structure of the full-length Piezo1 in an asymmetric membrane. A 18 number of novel insights emerge: (i) Piezo1 creates a dome in the membrane with a trilobed 19 topology that extends beyond the radius of the protein, (ii) Piezo1 changes the lipid 20 environment in its vicinity via specific interactions with cholesterol and PIP2 molecules, (iii) 21 changes in cholesterol concentration that change the membrane stiffness result in changes in 22 the depth of the dome created by Piezo1, and iv) modelling of the N-terminal region that is 23 missing from current structures modifies Piezo1 membrane footprint, suggesting the 24 importance of this region in Piezo1 function. 25

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confidence: 77%

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confidence: 84%

Computational reconstruction of the complete Piezo1 structure reveals a unique footprint and specific lipid interactions

Chong

Vecchis

Hyman

et al. 2019

Preprint

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“…Certainly, the pattern of Ca 2+ activation in the HFF cells in the vicinity of adhesions is consistent with previous results 22,37,38 , but it is not consistent with the simplistic model of very high membrane tension for the whole cell. Rather, there appear to be local activation events that involve elements from the adhesions that may alter local membrane tension/curvature or the association of membrane/cytoskeletal proteins that can modulate the mechanical gating of Piezo1 activity [39][40][41] .…”

Section: Discussionmentioning

confidence: 99%

“…Since the discovery of Piezo1's role as a mechanosensitive ion channel in eukaryotic cells, the regulation mechanism of Piezo1's function in the various physiological activities of cells has been under heavy investigation 8,9 . The current model of Piezo1's physiological function assumes that it is diffusive in the plasma membrane and is activated locally through membrane bilayer tension or curvature changes that occur through cytoskeletal-dependent mechanical events 13,15,17,40,42 . In these studies, we find that the involvement of Piezo1 in cell spreading on fibronectin is lost with cell transformation and also with spreading on collagen.…”

Section: Discussionmentioning

confidence: 99%

Force-dependent recruitment of Piezo1 drives adhesion maturation and calcium entry in normal but not tumor cells

Yao

Tijore

Cox

et al. 2020

Preprint

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Piezo1 is a mechanosensitive Ca 2+ -permeable channel that has been implicated in a number of mechanosensing processes. It is diffusive on plasma membranes and activated by local membrane tension changes yet recent data suggest that Piezo1 activity is tightly coupled to the integrin-mediated actin cytoskeleton through a poorly understood mechanism. In our studies, we found that Piezo1 stably localizes to RGD matrix adhesions in normal but not in transformed cells. Piezo1 binding requires contractility and triggers local Ca 2+ entry during adhesion formation and turnover. In transformed cells, Piezo1 level does not affect adhesion morphology; and there is no detectable Ca 2+ influx around adhesions. Based upon these findings, we suggest that Piezo1 is a novel component of integrin-based adhesions in non-transformed cells and contributes to the distinct mechanosensing and Ca 2+ signaling in normal vs transformed cells.Concentration of Piezo1 at adhesions is a key factor underlying Piezo1's physiological functions.

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“…In this non-conducting conformation, the arms are arranged in tri-dimensional spirals, giving Piezos a triskelion, or propeller-like, shape when viewed perpendicularly to the membrane plane and a bowl-like shape when viewed parallel to it. This curvature around the Piezo arms creates a local curvature, or dome, in the lipid bilayer, suggests the arms sense mechanical forces transmitted from lipids by sensing tension-induced flattening of the membrane ( 6, 9, 10 ).…”

Section: Introductionmentioning

confidence: 99%

A Piezo1 Open State Reveals a Multi-fenestrated Ion Permeation Pathway

Jiang

Rosario

Botello‐Smith

et al. 2020

Preprint

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19Force-sensing Piezo channels are essential to many aspects of vertebrate physiology. Activation 20 of Piezo1 is facilitated by the presence of negative membrane lipids in the inner leaflet, such as 21 phosphatidylinositol-4,5-bisphosphate (PIP2). Here, to study how Piezo1 opens, we performed 22 tension) POPC membrane (11). We also showed that the dome rapidly flattens when membrane 60 tension is gradually increased. Despite flattening of the arms, however, the pore did not open. 61Since the Piezo1 arms are anticipated to act as mechanical levers, the shorter arms in our 62 truncated model may reduce the output force (on the pore) to the input effort (arm motion). 63Another possibility for the absence of opening motions in the pore may have come from the 64 symmetric property of our simulated bilayer: indeed, electrophysiological recordings showed 65 Piezo1 remains fully closed when reconstituted in symmetrical bilayers but spontaneously opens 66 in asymmetric bilayers containing dioleoyl-sn-glycero-3-phosphatidic acid (DOPA) or 67 lysophosphatidic acid (LPA) in the inner leaflet (12, 13). DOPA and LPA differ in the number of 68 fatty acid tails but are both negatively-charged. Interestingly, the presence of negatively-charged 69 PIP2 or phosphatidylserine (PS) lipids in the inner leaflet also promote channel activation (14-16). 70We thus reasoned that adding the missing arm regions and adding negatively charged PIP2 lipids 71 in the inner leaflet will allow us to computationally capture a Piezo1 open state. 72 73 74RESULTS 75 Piezo1 clustering induces flattening of the Piezo arms 76Our previous proof-of-concept AA simulation showed that the membrane curvature, or lipid dome, 77 imposed by the resting conformation of a truncated Piezo1 takes place over 3 μs (11). To reduce 78 computational time, here we first used a 12 μs Coarse-Grained (CG) Martini simulation to enable 79 rapid lipid diffusion and dome formation while the Piezo1 backbone was kept rigid. We performed 80 these CG simulations on both a symmetrical POPC membrane (PC:PC) and an asymmetrical 81 POPC membrane containing 5% PIP2 in the inner leaflet (PC:PC/PIP2) (Figure 1a, systems I and 82 II). The CG systems were then mapped back to an AA system and simulated it for an additional 83 2 μs (Figure 1a, systems III and IV). In all MD simulations with explicit solvent, the periodic 84 boundary conditions (PBC) create an infinite lattice where the simulated system is infinitely 85

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Force-induced conformational changes in PIEZO1

Cited by 235 publications

References 45 publications

Computational reconstruction of the complete Piezo1 structure reveals a unique footprint and specific lipid interactions

Computational reconstruction of the complete Piezo1 structure reveals a unique footprint and specific lipid interactions

Force-dependent recruitment of Piezo1 drives adhesion maturation and calcium entry in normal but not tumor cells

A Piezo1 Open State Reveals a Multi-fenestrated Ion Permeation Pathway

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