Structure of the mechanosensitive OSCA channels

Zhang, Mingfeng; Wang, Dali; Kang, Yimin; Wu, Jing-Xiang; Yao, Fuqiang; Pan, Chengfang; Yan, Zhiqiang; Song, Chen; Chen, Lei

doi:10.1038/s41594-018-0117-6

Cited by 160 publications

(260 citation statements)

References 67 publications

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“…Nonetheless, the detailed gating mechanism of this unique tethered ion channel remains unclear to date. Additionally, the membrane-surface-tension-induced ion channel gating provided a mechanism by which cells can respond to volume expansion (22)(23)(24)(25)(26), but there is no known mechano-gating mechanism that is able to respond to cell compression or volume shrinking. This work provides a plausible push-toopen mechanism for the tethered ion channels, which may be used by cells as a response to compression and shrinking.…”

mentioning

confidence: 99%

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

Wang

Guo

Liu

et al. 2019

Preprint

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NompC 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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confidence: 99%

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

Wang

Guo

Liu

et al. 2019

Preprint

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“…However, the electrophysiological properties of OSCA channels show some similarities to TREK channels [18]. Both have outward rectification properties, showing a "valvelike" channel behavior.…”

Section: Discussionmentioning

confidence: 97%

“…In eukaryotes, only members of the TREK channel subfamilies are mechanosensitive potassium channels negatively regulating the cell excitability [1]. Reported stretch-activated mechanosensitive channels include OSCAs [18], Piezos [15], K2Ps [3,19,20], TRPs [21,22], MscLs [23], and MscSs [24].…”

Section: Discussionmentioning

confidence: 99%

“…OSCA channels are dimer transporter-like family proteins. The M0 and M6 transmembrane helices of OSCA channels may play critical roles in channel mechanosensitivity [18]. Piezo channels are tetramers with long transmembrane helical units (THUs) assembled into a highly curved blade-like structure, and THUs may be involved in Piezo channel mechanosensitivity [25,26].…”

Section: Discussionmentioning

confidence: 99%

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Role of the Fourth Transmembrane Segment in TRAAK Channel Mechanosensitivity

Zhang

Yao

Chi

et al. 2018

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Mechanosensitive ion channels such as Piezo, TRAAK, TRPs and OSCA are important transmembrane proteins that are involved in many physiological processes such as touch, hearing and blood pressure regulation. Unlike ligand-gated channels or voltage-gated ion channels, which have a canonical ligand-binding domain or voltage-sensing domain, the mechanosensitive domain and related gating mechanism remain elusive. TRAAK channels are mechanosensitive channels that convert a physical mechanical force into a flow of potassium ions. The structures of TRAAK channels have been solved, however, the functional roles of the structural domains associated with channel mechanosensitivity remains unclear. Here, we generated a series of chimeric mutations between TRAAK and a non-mechanosensitive silent TWIK-1 K2P channel. We found that the selectivity filter region functions as the major gate of outward rectification and found that lower part of fourth transmembrane domain (M4) is necessary for TRAAK channel mechanosensitivity. We further demonstrated that upper part of M4 can modulate the mechanosensitivity of TRAAK channel. Furthermore, we found that hydrophilic substitutions of W262 and F121 facing each other, and hydrophobic substitutions of Q258 and G124, which are above and below W262 and F121, respectively, greatly increase mechanosensitivity, which suggests that dynamic interactions in the upper part of M4 and PH1 domain are involved in TRAAK channel mechanosensitivity. Interestingly, these gain-of-function mutations are sensitive to cell-poking stimuli, indicating that cell-poking stimuli generate a low membrane mechanical force that opens TRAAK channels. Our results thus showed that fourth transmembrane domain of TRAAK is critical for the gating of TRAAK by mechanical force and suggested that multiple dynamic interactions in the upper part of M4 and PH1 domain are involved in this process.

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“…[9] Investigation of the conserved domain architecture among these transporters revealed the existence of orthologs present in various taxonomic groups, such as fungi, green algae, plants, birds and mammals, which suggests the functional conservation of this family throughout higher eukaryotes. With the availability of sequences of various ANO superfamily members and the recently reported 3D structures of some OSCA proteins in Arabidopsis thaliana [4][5][6] it is possible to get an insight into the structural aspects of TMEM63B domains involved in the ion translocation across the membrane.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of osmosensitive Ca²⁺-activated channel TMEM63B promotes migration in HEK293T cells

Marques

Albuquerque

Vaz

et al. 2019

Preprint

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The recent discovery of the osmosensitive calcium (Ca 2+ ) channel OSCA has revealed the potential mechanism by which plant cells sense diverse stimuli. Osmosensory transporters and mechanosensitive channels can detect and respond to osmotic shifts that play an important role in active cell homeostasis. TMEM63 family of proteins are described as the closest homologues of OSCAs. Here, we characterize TMEM63B, a mammalian homologue of OSCAs, recently classified as mechanosensitive. In HEK293T cells TMEM63B localizes to the plasma membrane and is associated to F-actin. This Ca 2+ -activated channel specifically induces Ca 2+ influx across the membrane in response to extracellular Ca 2+ concentration and hyperosmolarity. In addition, overexpression of TMEM63B in HEK293T cells significantly enhanced cell migration and wound healing. The link between Ca 2+ osmosensitivity and cell migration might help to establish TMEM63B's pathogenesis, for example in cancer in which it is frequently overexpressed.

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Structure of the mechanosensitive OSCA channels

Cited by 160 publications

References 67 publications

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

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

Role of the Fourth Transmembrane Segment in TRAAK Channel Mechanosensitivity

Overexpression of osmosensitive Ca²⁺-activated channel TMEM63B promotes migration in HEK293T cells

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Structure of the mechanosensitive OSCA channels

Cited by 160 publications

References 67 publications

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

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

Role of the Fourth Transmembrane Segment in TRAAK Channel Mechanosensitivity

Overexpression of osmosensitive Ca2+-activated channel TMEM63B promotes migration in HEK293T cells

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Overexpression of osmosensitive Ca²⁺-activated channel TMEM63B promotes migration in HEK293T cells