Structural Insights into the Venus flytrap Mechanosensitive Ion Channel Flycatcher1

Flycatcher1 (FLYC1), a MscS homolog, has recently been identified as a candidate mechanosensitive (MS) ion channel involved in Venus flytrap prey recognition. FLYC1 is larger and its sequence diverges from previously studied MscS homologs, suggesting it has unique structural features that contribute to its function. Here, we characterized FLYC1 by cryo-electron microscopy, molecular dynamics simulations, and electrophysiology. Akin to bacterial MscS and plant MSL1 channels, we find that FLYC1 central core includes side portals in the cytoplasmic cage that regulate ion conduction, by identifying critical residues that modulate channel conductance. Topologically unique cytoplasmic flanking regions can adopt 'up' or 'down' conformations, making the channel asymmetric. Disruption of an up conformation-specific interaction severely delays channel deactivation by 40-fold likely due to stabilization of the channel open state. Our results illustrate novel structural features and likely conformational transitions that regulate mechano-gating of FLYC1.

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Structural Insights into a Plant Mechanosensitive Ion Channel MSL1

Cell Reports ◽

10.1016/j.celrep.2020.03.026 ◽

2020 ◽

Vol 30 (13) ◽

pp. 4518-4527.e3 ◽

Cited By ~ 5

Author(s):

Yawen Li ◽

Yufei Hu ◽

Jiawei Wang ◽

Xin Liu ◽

Wei Zhang ◽

...

Keyword(s):

Ion Channel ◽

Mechanosensitive Ion Channel ◽

Structural Insights

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The push-to-open mechanism of the tethered mechanosensitive ion channel NompC

eLife ◽

10.7554/elife.58388 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yang Wang ◽

Yifeng Guo ◽

Guanluan Li ◽

Chunhong Liu ◽

Lei Wang ◽

...

Keyword(s):

Ion Channel ◽

Transient Receptor Potential ◽

Trp Channels ◽

Receptor Potential ◽

Ankyrin Repeat ◽

Gating Mechanism ◽

Repeat Domain ◽

Mechanosensitive Ion Channel ◽

Transient Receptor ◽

Dynamics Simulations

NompC is a mechanosensitive ion channel responsible for the sensation of touch and balance in Drosophila melanogaster. Based on a resolved cryo-EM structure, we performed all-atom molecular dynamics simulations and electrophysiological experiments to study the atomistic details of NompC gating. Our results showed that NompC could be opened by compression of the intracellular ankyrin repeat domain but not by a stretch, and a number of hydrogen bonds along the force convey pathway are important for the mechanosensitivity. Under intracellular compression, the bundled ankyrin repeat region acts like a spring with a spring constant of ~13 pN nm−1 by transferring forces at a rate of ~1.8 nm ps−1. The linker helix region acts as a bridge between the ankyrin repeats and the transient receptor potential (TRP) domain, which passes on the pushing force to the TRP domain to undergo a clockwise rotation, resulting in the opening of the channel. This could be the universal gating mechanism of similar tethered mechanosensitive TRP channels, which enable cells to feel compression and shrinkage.

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Faculty Opinions recommendation of Structural Insights into a Plant Mechanosensitive Ion Channel MSL1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737654683.793574417 ◽

2020 ◽

Author(s):

Bettina Böttcher

Keyword(s):

Ion Channel ◽

Mechanosensitive Ion Channel ◽

Structural Insights

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Push-to-open: The Gating Mechanism of the Tethered Mechanosensitive Ion Channel NompC

10.1101/853721 ◽

2019 ◽

Cited By ~ 2

Author(s):

Yang Wang ◽

Yifeng Guo ◽

Chunhong Liu ◽

Lei Wang ◽

Aihua Zhang ◽

...

Keyword(s):

Ion Channels ◽

Ion Channel ◽

Mechanical Force ◽

Loss Of Function ◽

Mechanosensitive Ion Channels ◽

Gating Model ◽

Gating Mechanism ◽

Mechanosensitive Ion Channel ◽

Significant Conformational Change ◽

Dynamics Simulations

AbstractNompC was one of the earliest identified mechanosensitive ion channels responsible for the sensation of touch and balance in Drosophila melanogaster. A tethered gating model was proposed for NompC and the Cryo-EM structure has been solved. However, the atomistic mechano-gating mechanism still remains elusive. Here we show the atomistic details of the NompC channel opening in response to the compression of the intracellular domain while remaining closed under an intracellular stretch. This is demonstrated by all-atom molecular dynamics simulations and evidenced by electrophysiological experiments. Under intracellular compression, the ankyrin repeat region undergoes a significant conformational change and passes the mechanical force to the linker helices like a spring with a force constant of ~3.3 pN/nm. The linker helix region acts as a bridge between the ankyrin repeats and TRP domain, and most of the mutations breaking the hydrogen bonds around this region lead to the loss-of-function of the channel. Eventually, the compression-induced mechanical force is passed from the linker helices onto the TRP domain, which then undergoes a clockwise rotation that leads to the opening of the channel. This work provides a clear picture of how a pushing force opens the mechanosensitive ion channel NompC, which might be a universal gating mechanism of similar tethered mechanosensitive ion channels, enabling cells to feel and respond to compression or shrinking.

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Faculty Opinions recommendation of TACAN is an essential component of the mechanosensitive ion channel responsible for pain sensing.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733724857.793549081 ◽

2018 ◽

Author(s):

Eric Lingueglia

Keyword(s):

Ion Channel ◽

Essential Component ◽

Mechanosensitive Ion Channel

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Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1

Scientific Reports ◽

10.1038/s41598-017-04367-4 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

K. M. Lawrence ◽

R. C. Jones ◽

T. R. Jackson ◽

R. L. Baylie ◽

B. Abbott ◽

...

Keyword(s):

Ion Channel ◽

Mechanosensitive Ion Channel

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Structural insights into the modulation of PDGF/PDGFR-β complexation by hyaluronan derivatives

Biological Chemistry ◽

10.1515/hsz-2021-0173 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Kanagasabai Balamurugan ◽

Linda Koehler ◽

Jan-Niklas Dürig ◽

Ute Hempel ◽

Jörg Rademann ◽

...

Keyword(s):

Growth Factor ◽

Cancer Progression ◽

Computational Analysis ◽

Vascular Endothelial ◽

Receptor Recognition ◽

Dynamics Simulations ◽

Endothelial Growth Factor ◽

Structural Insights ◽

Important Physiological Process ◽

Computational Predictions

Abstract Angiogenesis is an important physiological process playing a crucial role in wound healing and cancer progression. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are key players in angiogenesis. Based on previous findings regarding the modulation of VEGF activity by glycosaminoglycans (GAG), here we explore the interaction of hyaluronan (HA)-based GAG with PDGF and its receptor PDGFR-β by applying molecular modeling and dynamics simulations in combination with surface plasmon resonance (SPR). Computational analysis on the interaction of oligo-hyaluronan derivatives with different sulfation pattern and functionalization shows that these GAG interact with PDGF in relevant regions for receptor recognition, and that high sulfation as well as modification with the TAMRA group convey stronger binding. On the other hand, the studied oligo-hyaluronan derivatives are predicted to scarcely recognize PDGFR-β. SPR results are in line with the computational predictions regarding the binding pattern of HA tetrasaccharide (HA4) derivatives to PDGF and PDGFR-β. Furthermore, our experimental results also show that the complexation of PDGF to PDGFR-β can be modulated by HA4 derivatives. The results found open the path for considering HA4 derivatives as potential candidates to be exploited for modulation of the PDGF/PDGFR-β signaling system in angiogenesis and related disease conditions.

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Identification of the structural features of quinazoline derivatives as EGFR inhibitors using 3D-QSAR modeling, molecular docking, molecular dynamics simulations and free energy calculations

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2021.1956591 ◽

2021 ◽

pp. 1-16

Author(s):

Fangfang Wang ◽

Wei Yang ◽

Hongping Liu ◽

Bo Zhou

Keyword(s):

Molecular Dynamics ◽

Free Energy ◽

Molecular Docking ◽

Molecular Dynamics Simulations ◽

3D Qsar ◽

Structural Features ◽

Free Energy Calculations ◽

Qsar Modeling ◽

Quinazoline Derivatives ◽

Dynamics Simulations

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Cluster, Surface and Bulk Properties of ZnCd Binary Alloys: Molecular-Dynamics Simulations

Materials Science Forum ◽

10.4028/www.scientific.net/msf.502.51 ◽

2005 ◽

Vol 502 ◽

pp. 51-56 ◽

Cited By ~ 1

Author(s):

Sakir Erkoc

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Density Functional ◽

Structural Features ◽

Bulk Materials ◽

Bulk Properties ◽

Atom Clusters ◽

Dynamics Simulations ◽

Mixed Clusters ◽

Stable Structures

The structural and electronic properties of isolated neutral ZnmCdn clusters for m+n £ 3 have been investigated by performing density functional theory calculations at B3LYP level. The optimum geometries, vibrational frequencies, electronic structures, and the possible dissosiation channels of the clusters considered have been obtained. An empirical many-body potential energy function (PEF), which comprices two- and three-body atomic interactions, has been developed to investigate the structural features and energetics of ZnmCdn (m+n=3,4) microclusters. The most stable structures were found to be triangular for the three-atom clusters and tetrahedral for the four-atom clusters. On the other hand, the structural features and energetics of Znn-mCdm (n=7,8) microclusters, and Zn50, Cd50, Zn25Cd25, Zn12Cd38, and Zn38Cd12 nanoparticles have been investigated by performing molecular-dynamics computer simulations using the developed PEF. The most stable structures were found to be compact and three-dimensional for all elemental and mixed clusters. An interesting structural feature of the mixed clusters is that Zn and Cd atoms do not mix in mixed clusters, they come together almost without mixing. Surface and bulk properties of Zn, Cd, and ZnCd systems have been investigated too by performing molecular-dynamics simulations using the developed PEF. Surface reconstruction and multilayer relaxation on clean surfaces, adatom on surface, substitutional atom on surface and bulk materials, and vacancy on surface and bulk materials have been studied extensively.

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