A mechanism for the activation of the mechanosensitive Piezo1 channel by the small molecule Yoda1

Botello‐Smith, Wesley M.; Jiang, Wenjuan; Zhang, Han; Özkan, Alper D.; Lin, Yi‐Chun; Pham, Christine N.; Lacroix, Jérôme J.; Luo, Yang

doi:10.1038/s41467-019-12501-1

Cited by 171 publications

(199 citation statements)

References 56 publications

(64 reference statements)

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“…The Piezo1 conformational changes induced by channel clustering has two major components: a flattening of the whole arm when viewed parallel to the membrane and a straightening of the proximal N-terminal region (rotation around the elbow) when viewed perpendicular to the membrane ( Figure 1d ). These conformational changes observed here due to membrane flattening are similar to the ones observed from a truncated Piezo1 simulation when applying membrane tension ( 11 ). There are three helical bundles (Piezo repeats) on the N-terminal peripheral region of the arms not present in Piezo1 cryo-EM structures.…”

Section: Discussionsupporting

confidence: 83%

“…Our previous proof-of-concept AA simulation showed that the membrane curvature, or lipid dome, imposed by the resting conformation of a truncated Piezo1 takes place over 3 μs ( 11 ). To reduce computational time, here we first used a 12 μs Coarse-Grained (CG) Martini simulation to enable rapid lipid diffusion and dome formation while the Piezo1 backbone was kept rigid.…”

Section: Resultsmentioning

confidence: 99%

“…The CG representation of Piezo 1 was constructed from our previously all-atom mouse Piezo1 model based on the cryo-EM structure (PDB ID 6B3R), which includes residue 782–1365 (Piezo repeat C-F and beam), 1493–1578 (clasp), 1655–1807 (repeat B), and 1952–2546 (repeat A, anchor, TM37, cap, TM38, and CTD) ( 11 ). Based on these atomistic coordinates, the coarse-grained model using MARTINI v2.2 force field was obtained through the script martinize.py and insane.py available from the MARTINI web site ( 40-42 ).…”

Section: Methodsmentioning

confidence: 99%

“…Using all-atom (AA) molecular dynamics (MD) simulations, we have recently shown that a truncated Piezo1 computational model spontaneously creates the lipid dome in a relaxed (zero tension) POPC membrane ( 11 ). We also showed that the dome rapidly flattens when membrane tension is gradually increased.…”

Section: Introductionmentioning

confidence: 99%

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

Jiang

Rosario

Botello‐Smith

et al. 2020

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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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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Jiang

Rosario

Botello‐Smith

et al. 2020

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“…Finally, the extended structure obtained at −40 bar is corroborated by recent structural data which positively correlate the size of the vesicle with a flattened Piezo1 structure13. Flattening of Piezo1 may also be needed for Yoda1 binding 17 .…”

Section: Tension Causes Piezo1 To Flatten and Expandmentioning

confidence: 99%

Molecular principles of Piezo1 activation by increased membrane tension

Vecchis

Beech

Kalli

2019

Preprint

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11 SUMMARY PARAGRAPH 12 13Piezo1 is a mechanosensitive channel involved in many cellular functions and responsible for 14 sensing shear-stress and pressure forces in cells1-3. Piezo1 plays a critical role in the circulatory 15 system and tissue development. Mutations on Piezo1 are linked to human diseases such as 16 lymphedema2,4 or hematological disorders such as hemolytic anaemia5 and resistance to 17 malaria6. Hypotheses for Piezo1 gating include the "force-from-lipids" principle7,8 that 18 suggests that Piezo1 senses mechanical forces through the bilayer1,9 and a direct involvement 19 of the cytoskeleton as well as the extracellular matrix in Piezo1 activation10,11. However, the 20 molecular and structural changes underpinning the Piezo1 gating mechanism and how the 21 channel senses forces in the membrane remain unknown. Here we reveal the activation 22 mechanism of Piezo1 and the structural rearrangements that occur when Piezo1 moves from a 23closed to an open state when mechanical tension is applied to the cell membrane. Our results 24show that Piezo1's curved shape is stable in a native-like model membrane without tension 25 creating a membrane indentation with a trilobed topology. Upon stretching Piezo1 adapts to 26 the stretched bilayer by flattening and expansion of its blade region. In our simulations Piezo1 27 expands up to a planar circular area of ~680 nm 2 comparable with previous structural data and 28 hypotheses12-14. Piezo1 flattening and expansion results in changes in the beam helix tilt angle. 29 These movements result in the tilting and lateral movement of the pore lining TM37 and TM38 30 helices. This leads to the opening of the channel and to the movement of lipids that occupy 31 Piezo1 pore region outside of this region, revealing for the first time the structural changes that 32 happen during Piezo1 mechanical activation. The changes in the blade region are transmitted 33 to helices TM37 and 38 via hydrophobic interactions and by interactions of neighbouring 34 2 subunits via the elbow region. The flat structure of Piezo1 identified in this study exposes the 35 C-terminal extracellular domain (CED) that in the closed state is hidden in the membrane and 36 presumably from shear stress. Our results provide new structural data for different states of 37 Piezo1 and suggest the molecular principles by which mechanical force opens the Piezo1 38 channel, thus coupling force to physiological effect via ion permeation. 39 40 41 using the protein Cα of the C-terminal extracellular domain (CED), dashed lines (lower values), and 48 of the rest of the protein (i.e. the Piezo1 blades), straight lines (higher values). (d) Projected area of 49 the Piezo1 membrane indentation on the membrane plane (Aproj, indicated by a dashed blue circle in 50 a) as a function of time. For the -40 system the timeline is the average between the two repeats. The 51 standard deviation is indicated. 52 53To investigate how mechanical forces act on the Piezo1 channel, we simulated the recent Piezo1 54 structure solved by cr...

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4D Oriented Dynamic Scaffold for Promoting Peripheral Nerve Regeneration and Functional Recovery

Sun,

You,

Zhan

et al. 2023

Adv Funct Materials

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Neurological function recovery after peripheral nerve injury (PNI) is exceptionally challenging, chiefly because neurons cannot efficiently proliferate, differentiate, and form regenerated axons to pass through the defect region expeditiously and transmit neurological signals. In this study, a four‐dimensional (4D) oriented dynamic scaffold is constructed based on shape memory polymer (SMP), which can regulate spatiotemporally controllable neuronal early adequate proliferation, subsequently effective differentiation and axon formation by synergizing the on‐demand microtopography and deformation force‐based mechanical stimuli (DFMS). This dynamic scaffold can accelerate the restoration of large segmental nerve defects, elevate the neural signaling efficiency by 60% compared with static scaffold, and finally form the functionalized robust regenerating nerve fascicles with comparable therapeutic effects on autologous nerve transplantation. Furthermore, the crucial role of Piezo1/Camk2b modulated neuronal differentiation and axon extension is also revealed through deep transcriptomic analysis. In summary, the 4D oriented dynamic scaffold can precisely and remotely regulate neuronal behavior and fate in a non‐invasive way, which has excellent potential for clinical application in peripheral nerve restoration.

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A mechanism for the activation of the mechanosensitive Piezo1 channel by the small molecule Yoda1

Cited by 171 publications

References 56 publications

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

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

Molecular principles of Piezo1 activation by increased membrane tension

4D Oriented Dynamic Scaffold for Promoting Peripheral Nerve Regeneration and Functional Recovery

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