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

Chong, Jiehan; Vecchis, Dario De; Hyman, Adam J.; Povstyan, Oleksandr V.; Shi, Jing; Beech, David J; Kalli, Antreas C.

doi:10.1101/783753

Cited by 5 publications

(13 citation statements)

References 73 publications

(122 reference statements)

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“…However, the similarity and repetitive nature of nearby regions suggested the possibility to predict the entire protein structure, which we did (Figure 3) 22 . Validity of the model was supported by close overlay with the related mouse PIEZO2 22 , for which complete experimentally-derived structural data exist 37 . Viewing our modelled PIEZO1 from the extracellular space shows the expected trimeric arrangement of the 3 PIEZO1s required to form a PIEZO1 ion channel ( Figure 3A).…”

Section: Prediction Of An Outward-facing Interaction Sitementioning

confidence: 64%

“…While we have insight into how some parts of the PIEZO1 molecular machine operate 21,42,43 , the particular region of PIEZO1 incorporating V or A at position 250 is uncharted territory 22 . Based on our molecular modelling we suggest that V250A forms part of an outward-facing domain at the tip of the propeller blades, along with the other residues affected by SNPs (I83 and P152) ( Figure 3A).…”

Section: Discussionmentioning

confidence: 99%

“…Based on our molecular modelling we suggest that V250A forms part of an outward-facing domain at the tip of the propeller blades, along with the other residues affected by SNPs (I83 and P152) ( Figure 3A). Such a domain seems ideally placed to interact with nearby proteins but could also be important in refining mechanical sensitivity and how the channel interacts with lipids 22 . The molecular and functional studies required to test these ideas will take time to complete.…”

Section: Discussionmentioning

confidence: 99%

“…While we have insight into how some parts of the PIEZO1 molecular machine operate 19,35,40 , the particular region of PIEZO1 incorporating V or A at position 250 is uncharted territory 20 . Progress with cryo-EM techniques has led to structural information 19,35 but the N-terminal region has not been resolved, possibly because it has highly flexible structural conformations.…”

Section: Discussionmentioning

confidence: 99%

“…This protein forms Ca 2+ -permeable non-selective cation channels that have extraordinary capability to respond to membrane tension 18 and shear stress caused by fluid flow along the endothelial membrane surface 16 . Unusually for membrane proteins, PIEZO1 indents the membrane in an inverted dome-like fashion and therefore modifies the overall structure of the membrane 19,20 . The channel shows marked activity in mesenteric endothelium 21 and there is increasing evidence of its importance in many aspects of endothelial function, such as angiogenesis 16,22 and pulmonary vascular permeability 23,24 .…”

Section: Introductionmentioning

confidence: 99%

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Genetic variants of PIEZO1 associate with COVID-19 fatality

Cheng

Deivasikamani

Ludlow

et al. 2020

Preprint

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COVID-19, caused by the SARS-CoV-2 virus, carries significant risk of mortality and has spread globally with devastating societal consequences. Endothelial infection has been identified as a feature of the disease and so there is motivation to determine the relevance of endothelial membrane mechanisms affecting viral entry and response. Here, through a study of patient data in UK Biobank released on 16 April 2020, we suggest relevance of PIEZO1, a non-selective cation channel protein that both mediates endothelial responses to mechanical force and unusually indents the cell membrane. PIEZO1 notably has roles that may also be relevant in red blood cell function, pulmonary inflammation, bacterial infection and fibrotic auto-inflammation. We provide evidence that single nucleotide polymorphisms (SNPs) in the gene encoding PIEZO1 are more common in individuals who test positive for SARS-CoV-2 regardless of pre-existing hypertension, myocardial infarction, stroke, diabetes mellitus or arthritis. Some of these SNPs are more common in African and Caribbean populations, which are groups that were recently shown to have greater susceptibility to infection. One of the SNPs is a missense mutation that results in an amino acid change in an evolutionarily conserved and previously unexplored N-terminal region PIEZO1. The data support the notion of genetic factors influencing SARS-CoV-2 infection and suggest a specific role for PIEZO1.

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Section: Prediction Of An Outward-facing Interaction Sitementioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genetic variants of PIEZO1 associate with COVID-19 fatality

Cheng

Deivasikamani

Ludlow

et al. 2020

Preprint

Self Cite

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Molecular dynamics simulations of Piezo1 channel opening by increases in membrane tension

Vecchis

Beech

Kalli

2021

Biophysical Journal

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Piezo1 is a mechanosensitive channel involved in many cellular functions and responsible for sensing shear stress and pressure forces in cells. Piezo1 has a unique trilobed topology with a curved membrane region in the closed state. It has been suggested that upon activation Piezo1 adopts a flattened conformation, but the molecular and structural changes underpinning the Piezo1 gating and opening mechanisms and how the channel senses forces in the membrane remain elusive. Here, we used molecular dynamics simulations to reveal the structural rearrangements that occur when Piezo1 moves from a closed to an open state in response to increased mechanical tension applied to a model membrane. We find that membrane stretching causes Piezo1 to flatten and expand its blade region, resulting in tilting and lateral movement of the pore-lining transmembrane helices 37 and 38. This is associated with the opening of the channel and movement of lipids out of the pore region. Our results reveal that because of the rather loose packing of Piezo1 pore region, movement of the lipids outside the pore region is critical for the opening of the pore. Our simulations also suggest synchronous flattening of the Piezo1 blades during Piezo1 activation. The flattened structure lifts the C-terminal extracellular domain up, exposing it more to the extracellular space. Our studies support the idea that it is the blade region of Piezo1 that senses tension in the membrane because pore opening failed in the absence of the blades. Additionally, our simulations reveal that upon opening, water molecules occupy lateral fenestrations in the cytosolic region of Piezo1, which might be likely paths for ion permeation. Our results provide a model for how mechanical force opens the Piezo1 channel and thus how it might couple mechanical force to biological response.

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Sphingomyelinase Disables Inactivation in Endogenous PIEZO1 Channels

et al. 2020

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Summary Endogenous PIEZO1 channels of native endothelium lack the hallmark inactivation often seen when these channels are overexpressed in cell lines. Because prior work showed that the force of shear stress activates sphingomyelinase in endothelium, we considered if sphingomyelinase is relevant to endogenous PIEZO1. Patch clamping was used to quantify PIEZO1-mediated signals in freshly isolated murine endothelium exposed to the mechanical forces caused by shear stress and membrane stretch. Neutral sphingomyelinase inhibitors and genetic disruption of sphingomyelin phosphodiesterase 3 (SMPD3) cause PIEZO1 to switch to profoundly inactivating behavior. Ceramide (a key product of SMPD3) rescues non-inactivating channel behavior. Its co-product, phosphoryl choline, has no effect. In contrast to ceramide, sphingomyelin (the SMPD3 substrate) does not affect inactivation but alters channel force sensitivity. The data suggest that sphingomyelinase activity, ceramide, and sphingomyelin are determinants of native PIEZO gating that enable sustained activity.

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

Cited by 5 publications

References 73 publications

Genetic variants of PIEZO1 associate with COVID-19 fatality

Genetic variants of PIEZO1 associate with COVID-19 fatality

Molecular dynamics simulations of Piezo1 channel opening by increases in membrane tension

Sphingomyelinase Disables Inactivation in Endogenous PIEZO1 Channels

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