Brunner, J. D., Lim, N. K., Schenck, S., Duerst, A. & Dutzler, R. X-ray structure of a calcium-activated TMEM16 lipid scramblase. Nature 516, 207–212 (2014). The first structure of a TMEM16 family member, the crystal structure of the dimeric nhTMEM16 from the fungus Nectria haematococca, reveals a novel protein fold in each monomer that contains Ca2+-binding sites within the hydrophobic core of the membrane.
Article CAS PubMed Google Scholar
Paulino, C. et al. Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A. eLife 6, e26232 (2017).
Article PubMed Central PubMed Google Scholar
Paulino, C., Kalienkova, V., Lam, A. K. M., Neldner, Y. & Dutzler, R. Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM. Nature 552, 421–425 (2017).
Article CAS PubMed Google Scholar
Dang, S. et al. Cryo-EM structures of the TMEM16A calcium-activated chloride channel. Nature 552, 426–429 (2017).
Article CAS PubMed Central PubMed Google Scholar
Lam, A. K. M., Rutz, S. & Dutzler, R. Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC. Nat. Commun. 13, 2798 (2022).
Article CAS PubMed Central PubMed Google Scholar
Alvadia, C. et al. Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F. eLife 8, e44365 (2019).
Article PubMed Central PubMed Google Scholar
Feng, S. et al. Cryo-EM studies of TMEM16F calcium-activated ion channel suggest features important for lipid scrambling. Cell Rep. 28, 567–579 (2019).
Arndt, M. et al. Structural basis for the activation of the lipid scramblase TMEM16F. Nat. Commun. 13, 6692 (2022).
Article CAS PubMed Central PubMed Google Scholar
Feng, S. et al. Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase. Nat. Commun. 14, 4874 (2023). Cryo-EM studies of TMEM16F Ca2+-activated ion channel and lipid scramblase revealing a lipid trail outside the ion permeation pore, in a groove that harbors the binding pocket for niclosamide, provide support for separate pathways for ion permeation and lipid scrambling.
Article CAS PubMed Central PubMed Google Scholar
Bushell, S. R. et al. The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K. Nat. Commun. 10, 3956 (2019).
Article PubMed Central PubMed Google Scholar
Jeong, H. et al. Structures of the TMC-1 complex illuminate mechanosensory transduction. Nature 610, 796–803 (2022). Cryo-EM structures of the native TMC-1 mechanosensory transduction complex containing the Ca2+-binding protein CALM-1 and TMIE reveal membrane deformation.
Article CAS PubMed Central PubMed Google Scholar
Clark, S., Jeong, H., Posert, R., Goehring, A. & Gouaux, E. The structure of the Caenorhabditis elegans TMC-2 complex suggests roles of lipid-mediated subunit contacts in mechanosensory transduction. Proc. Natl Acad. Sci. USA 121, e2314096121 (2024).
Article CAS PubMed Central PubMed Google Scholar
Zhang, M. et al. Structure of the mechanosensitive OSCA channels. Nat. Struct. Mol. Biol. 25, 850–858 (2018).
Article CAS PubMed Google Scholar
Murthy, S. E. et al. OSCA/TMEM63 are an evolutionarily conserved family of mechanically activated ion channels. eLife 7, e41844 (2018).
Article PubMed Central PubMed Google Scholar
Jojoa-Cruz, S. et al. Cryo-EM structure of the mechanically activated ion channel OSCA1.2. eLife 7, e41845 (2018).
Article PubMed Central PubMed Google Scholar
Liu, X., Wang, J. & Sun, L. Structure of the hyperosmolality-gated calcium-permeable channel OSCA1.2. Nat. Commun. 9, 5060 (2018).
Article PubMed Central PubMed Google Scholar
Maity, K. et al. Cryo-EM structure of OSCA1.2 from Oryza sativa elucidates the mechanical basis of potential membrane hyperosmolality gating. Proc. Natl Acad. Sci. USA 116, 14309–14318 (2019).
Article CAS PubMed Central PubMed Google Scholar
Zhang, M., Shan, Y., Cox, C. D. & Pei, D. A mechanical-coupling mechanism in OSCA/TMEM63 channel mechanosensitivity. Nat. Commun. 14, 3943 (2023).
Article CAS PubMed Central PubMed Google Scholar
Qin, Y. et al. Cryo-EM structure of TMEM63C suggests it functions as a monomer. Nat. Commun. 14, 7265 (2023).
Article CAS PubMed Central PubMed Google Scholar
Zheng, W. et al. TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels. Neuron 111, 3195–3210 (2023). TMEM63A and TMEM63B are monomeric mechanosensitive ion channels, while mechanosensitivity of OSCA1.2 channels is affected by oligomerization.
Article CAS PubMed Central PubMed Google Scholar
Copic, A., Dieudonne, T. & Lenoir, G. Phosphatidylserine transport in cell life and death. Curr. Opin. Cell Biol. 83, 102192 (2023).
Article CAS PubMed Google Scholar
Fujii, T., Sakata, A., Nishimura, S., Eto, K. & Nagata, S. TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets. Proc. Natl Acad. Sci. USA 112, 12800–12805 (2015).
Article CAS PubMed Central PubMed Google Scholar
Han, T. W. et al. Chemically induced vesiculation as a platform for studying TMEM16F activity. Proc. Natl Acad. Sci. USA 116, 1309–1318 (2019).
Article CAS PubMed Central PubMed Google Scholar
Margolis, L. & Sadovsky, Y. The biology of extracellular vesicles: the known unknowns. PLoS Biol. 17, e3000363 (2019).
Article CAS PubMed Central PubMed Google Scholar
Hargett, L. A. & Bauer, N. N. On the origin of microparticles: from ‘platelet dust’ to mediators of intercellular communication. Pulm. Circ. 3, 329–340 (2013).
Article PubMed Central PubMed Google Scholar
Ballesteros, A. & Swartz, K. J. Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing. Sci. Adv. 8, eabm5550 (2022). TMC1 channel dysfunction that results in reduced internal Ca2+levels causes TMC1-dependent PtdSer exposure and shedding of microvesicles for TMC1 removal from cochlear hair cell stereocilia.
Article CAS PubMed Central PubMed Google Scholar
Whitlock, J. M. & Chernomordik, L. V. Flagging fusion: phosphatidylserine signaling in cell–cell fusion. J. Biol. Chem. 296, 100411 (2021).
Article CAS PubMed Central PubMed Google Scholar
Zhang, Y. et al. TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development. Sci. Adv. 6, eaba0310 (2020). TMEM16F-mediated PtdSer exposure on placental trophoblasts is important for trophoblast syncytialization and placental development.
Article CAS PubMed Central PubMed Google Scholar
Braga, L. et al. Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia. Nature 594, 88–93 (2021). TMEM16F is required for cell fusion induced by the interaction between spike protein and its receptor ACE2 in syncytial formation, a prominent symptom of autopsies of individuals with COVID-19.
Article CAS PubMed Central PubMed Google Scholar
Rajah, M. M., Bernier, A., Buchrieser, J. & Schwartz, O. The mechanism and consequences of SARS-CoV-2 spike-mediated fusion and syncytia formation. J. Mol. Biol. 434,
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