Cryo-EM structures of the TMEM16A calcium-activated chloride channel
Open accessAbstract
Calcium-activated chloride channels (CaCCs) encoded by TMEM16A control neuronal signalling, smooth muscle contraction, airway and exocrine gland secretion, and rhythmic movements of the gastrointestinal system. To understand how CaCCs mediate and control anion permeation to fulfil these physiological functions, knowledge of the mammalian TMEM16A structure and identification of its pore-lining residues are essential. TMEM16A forms a dimer with two pores. Previous CaCC structural analyses have relied on homology modelling of a homologue (nhTMEM16) from the fungus Nectria haematococca that functions primarily as a lipid scramblase, as well as subnanometre-resolution electron cryo-microscopy. Here we present de novo atomic structures of the transmembrane domains of mouse TMEM16A in nanodiscs and in lauryl maltose neopentyl glycol as determined by single-particle electron cryo-microscopy. These structures reveal the ion permeation pore and represent different functional states. The structure in lauryl maltose neopentyl glycol has one Ca 2+ ion resolved within each monomer with a constricted pore; this is likely to correspond to a closed state, because a CaCC with a single Ca 2+ occupancy requires membrane depolarization in order to open (C.J.P. et al., manuscript submitted). The structure in nanodiscs has two Ca 2+ ions per monomer and its pore is in a closed conformation; this probably reflects channel rundown, which is the gradual loss of channel activity that follows prolonged CaCC activation in 1 mM Ca 2+. Our mutagenesis and electrophysiological studies, prompted by analyses of the structures, identified ten residues distributed along the pore that interact with permeant anions and affect anion selectivity, as well as seven pore-lining residues that cluster near pore constrictions and regulate channel gating. Together, these results clarify the basis of CaCC anion conduction.
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UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 45,260 · see citing works
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. D. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 27,510 · see citing works
<i>PHENIX</i> : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716 · see citing works
<i>MolProbity</i> : all-atom structure validation for macromolecular crystallography
Chen, V. B., Arendall, W. B., Headd, J. J., Keedy, D. A., Immormino, R. M., Kapral, G. J., Murray, L. W., Richardson, J. S., & Richardson, D. C. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909042073 · Cited by 14,115 · see citing works
MotionCor2 - anisotropic correction of beam-induced motion for improved cryo-electron microscopy
Zheng, S., Palovcak, E. J., Armache, J., Verba, K., Cheng, Y.-F., & Agard, D. (2017) · Nature Methods · doi:10.1038/nmeth.4193 · Cited by 7,678 · see citing works
Self-citationPHENIX: a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkòczi, G., Chen, V. B., Davis, I., Echols, N., Headd, J. J., Hung, L., Kapral, G. J., Grosse‐Kunstleve, R. W., et al. (2012) · International Tables for Crystallography · doi:10.1107/97809553602060000865 · Cited by 7,334 · see citing works
RELION: Implementation of a Bayesian approach to cryo-EM structure determination
Scheres, S. H. W. (2012) · Journal of Structural Biology · doi:10.1016/j.jsb.2012.09.006 · Cited by 5,446 · see citing works
Automated electron microscope tomography using robust prediction of specimen movements.
Mastronarde, D. (2005) · Journal of Structural Biology · doi:10.1016/j.jsb.2005.07.007 · Cited by 5,446 · see citing works
CTFFIND4: Fast and accurate defocus estimation from electron micrographs
Rohou, A. L., & Grigorieff, N. (2015) · Journal of Structural Biology · doi:10.1016/j.jsb.2015.08.008 · Cited by 4,926 · see citing works
Gctf: Real-time CTF determination and correction
Zhang, K. (2015) · Journal of Structural Biology · doi:10.1016/j.jsb.2015.11.003 · Cited by 3,372 · see citing works
EMAN2: An extensible image processing suite for electron microscopy
Tang, G., Peng, L., Baldwin, P. R., Mann, D. S., Jiang, W., Rees, I., & Ludtke, S. J. (2006) · Journal of Structural Biology · doi:10.1016/j.jsb.2006.05.009 · Cited by 2,914 · see citing works
Rosenthal, P. B., & Henderson, R. (2003) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.07.013 · Cited by 2,416 · see citing works
SPIDER and WEB: Processing and Visualization of Images in 3D Electron Microscopy and Related Fields
Frank, J., Radermacher, M., Penczek, P. A., Zhu, J., Li, Y., Ladjadj, M., & Leith, A. G. (1996) · Journal of Structural Biology · doi:10.1006/jsbi.1996.0030 · Cited by 2,026 · see citing works
HOLE: A program for the analysis of the pore dimensions of ion channel structural models
Smart, O. S., Neduvelil, J. G., Wang, X., Wallace, B. A., & Sansom, M. S. P. (1996) · Journal of Molecular Graphics · doi:10.1016/s0263-7855(97)00009-x · Cited by 1,803 · see citing works
Quantifying the local resolution of cryo-EM density maps
Kucukelbir, A., Sigworth, F. J., & Tagare, H. D. (2013) · Nature Methods · doi:10.1038/nmeth.2727 · Cited by 1,763 · see citing works
Structure of the TRPV1 ion channel determined by electron cryo-microscopy
Liao, M., Cao, E., Julius, D. J., & Cheng, Y. (2013) · Nature · doi:10.1038/nature12822 · Cited by 1,696 · see citing works
Self-citationTMEM16A confers receptor-activated calcium-dependent chloride conductance
Yang, Y. D., Cho, H., Koo, J. Y., Tak, M. H., Cho, Y., Shim, W., Park, S. P., Lee, J., Lee, B., KIM, B. M., et al. (2008) · Nature · doi:10.1038/nature07313 · Cited by 1,284 · see citing works
TMEM16A, A Membrane Protein Associated with Calcium-Dependent Chloride Channel Activity
Caputo, A., Caci, E., Ferrera, L., Pedemonte, N., Barsanti, C., Sondo, E., Pfeffer, U., Ravazzolo, R., Zegarra‐Moran, O., & Galietta, L. J. V. (2008) · Science · doi:10.1126/science.1163518 · Cited by 1,265 · see citing works
Prevention of overfitting in cryo-EM structure determination
Scheres, S. H. W., & Chen, S. (2012) · Nature Methods · doi:10.1038/nmeth.2115 · Cited by 1,204 · see citing works
Expression Cloning of TMEM16A as a Calcium-Activated Chloride Channel Subunit
Schroeder, B. C., Cheng, T., Jan, Y. N., & Jan, L. Y. (2008) · Cell · doi:10.1016/j.cell.2008.09.003 · Cited by 1,150 · see citing works
Self-citationAdjusted P-Values for Simultaneous Inference
Wright, S. P. (1992) · Biometrics · doi:10.2307/2532694 · Cited by 1,026 · see citing works
EMRinger: side chain–directed model and map validation for 3D cryo-electron microscopy
Barad, B. A., Echols, N., Wang, R. Y.-R., Cheng, Y., DiMaio, F., Adams, P. D., & Fraser, J. S. (2015) · Nature Methods · doi:10.1038/nmeth.3541 · Cited by 886 · see citing works
Self-citationKim, B. J., Nam, J., Kim, K. H., Joo, M., Ha, T. S., Weon, K.-Y., Choi, S., Jun, J. Y., Park, E., Wie, J., et al. (2014) · Cellular Physiology and Biochemistry · doi:10.1159/000366306 · Cited by 886 · see citing works
The correlation averaging of a regularly arranged bacterial cell envelope protein
Saxton, W. O., & Baumeister, W. (1982) · Journal of Microscopy · doi:10.1111/j.1365-2818.1982.tb00405.x · Cited by 874 · see citing works
Flexible Fitting of Atomic Structures into Electron Microscopy Maps Using Molecular Dynamics
Trabuco, L. G., Villa, E., Mitra, K., Frank, J., & Schulten, K. J. (2008) · Structure · doi:10.1016/j.str.2008.03.005 · Cited by 866 · see citing works
TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action
Gao, Y., Cao, E., Julius, D. J., & Cheng, Y. (2016) · Nature · doi:10.1038/nature17964 · Cited by 822 · see citing works
Self-citationScreening and large-scale expression of membrane proteins in mammalian cells for structural studies
Goehring, A., Lee, C.-H., Wang, K. H., Michel, J. C., Claxton, D. P., Baconguis, I., Althoff, T., Fischer, S., Garcia, K., & Gouaux, E. (2014) · Nature Protocols · doi:10.1038/nprot.2014.173 · Cited by 716 · see citing works
CALCIUM-ACTIVATED CHLORIDE CHANNELS
Hartzell, C., Putzier, I., & Arreola, J. (2004) · Annual Review of Physiology · doi:10.1146/annurev.physiol.67.032003.154341 · Cited by 627 · see citing works
Tools for macromolecular model building and refinement into electron cryo-microscopy reconstructions
Brown, A., Long, F., Nicholls, R. A., Toots, J., Emsley, P., & Murshudov, G. N. (2014) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s1399004714021683 · Cited by 621 · see citing works
Structure and Function of TMEM16 Proteins (Anoctamins)
Pedemonte, N., & Galietta, L. J. V. (2014) · Physiological Reviews · doi:10.1152/physrev.00039.2011 · Cited by 523 · see citing works
Yang, H., Kim, A., David, T., Palmer, D., Jin, T., Tien, J., Huang, F., Cheng, T., Coughlin, S. R., Jan, Y. N., et al. (2012) · Cell · doi:10.1016/j.cell.2012.07.036 · Cited by 470 · see citing works
Self-citationMicroscale Fluorescent Thermal Stability Assay for Membrane Proteins
Alexandrov, A. I., Mileni, M., Chien, E. Y. T., Hanson, M. A., & Stevens, R. C. (2008) · Structure · doi:10.1016/j.str.2008.02.004 · Cited by 451 · see citing works
X-ray structure of a calcium-activated TMEM16 lipid scramblase
Brunner, J. D., Lim, N. K., Schenck, S., Duerst, A., & Dutzler, R. (2014) · Nature · doi:10.1038/nature13984 · Cited by 437 · see citing works
Structure of the voltage-gated K + channel Eag1 reveals an alternative voltage sensing mechanism
Whicher, J. R., & MacKinnon, R. (2016) · Science · doi:10.1126/science.aaf8070 · Cited by 320 · see citing works
Identification of a lipid scrambling domain in ANO6/TMEM16F
Yu, K., Whitlock, J. M., Lee, K., Ortlund, E. A., Cui, Y., & Hartzell, H. C. (2015) · eLife · doi:10.7554/elife.06901 · Cited by 180 · see citing works
van Heel, M., & Stöffler-Meilicke, M. (1985) · The EMBO Journal · doi:10.1002/j.1460-2075.1985.tb03944.x · Cited by 178 · see citing works
Fabs Enable Single Particle cryoEM Studies of Small Proteins
Wu, S., Avila-Sakar, A., Kim, J., Booth, D. S., Greenberg, C. H., Rossi, A., Liao, M., Li, X., Alian, A., Griner, S. L., et al. (2012) · Structure · doi:10.1016/j.str.2012.02.017 · Cited by 178 · see citing works
Self-citationInternational Union of Basic and Clinical Pharmacology. LXXXV: Calcium-Activated Chloride Channels
Huang, F., Wong, X. M., & Jan, L. Y. (2011) · Pharmacological Reviews · doi:10.1124/pr.111.005009 · Cited by 173 · see citing works
Self-citationAnoctamins/TMEM16 Proteins: Chloride Channels Flirting with Lipids and Extracellular Vesicles
Whitlock, J. M., & Hartzell, H. C. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034031 · Cited by 165 · see citing works
Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A
Paulino, C., Neldner, Y., Lam, A. K. M., Kalienkova, V., Brunner, J. D., Schenck, S., & Dutzler, R. (2017) · eLife · doi:10.7554/elife.26232 · Cited by 164 · see citing works
Explaining Calcium-Dependent Gating of Anoctamin-1 Chloride Channels Requires a Revised Topology
Yu, K., Duran, C., Qu, Z., Cui, Y.-Y., & Hartzell, H. C. (2012) · Circulation Research · doi:10.1161/circresaha.112.264440 · Cited by 161 · see citing works
Cellular functions of TMEM16/anoctamin
Oh, U., & Jung, J. (2016) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-016-1790-0 · Cited by 161 · see citing works
Tien, J., Peters, C. J., Wong, X. M., Cheng, T., Jan, Y. N., Jan, L. Y., & Yang, H. (2014) · eLife · doi:10.7554/elife.02772 · Cited by 128 · see citing works
Self-citationLipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase
Jiang, T., Yu, K., Hartzell, H. C., & Tajkhorshid, E. (2017) · eLife · doi:10.7554/elife.28671 · Cited by 105 · see citing works
Peters, C. J., Gilchrist, J. M., Tien, J., Bethel, N. P., Qi, L., Chen, T., Wang, L., Jan, Y. N., Grabe, M., & Jan, L. Y. (2018) · Neuron · doi:10.1016/j.neuron.2018.01.048 · Cited by 91 · see citing works
Self-citationLim, N. K., Lam, A. K. M., & Dutzler, R. (2016) · The Journal of General Physiology · doi:10.1085/jgp.201611650 · Cited by 90 · see citing works
Peters, C. J., Yu, H., Tien, J., Jan, Y. N., Li, M., & Jan, L. Y. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1502291112 · Cited by 84 · see citing works
Self-citationIndependent activation of distinct pores in dimeric TMEM16A channels
Jeng, G., Aggarwal, M., Yu, W.-P., & Chen, T. (2016) · The Journal of General Physiology · doi:10.1085/jgp.201611651 · Cited by 80 · see citing works
Self-citationStructural basis for phospholipid scrambling in the TMEM16 family
Brunner, J. D., Schenck, S., & Dutzler, R. (2016) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2016.05.020 · Cited by 71 · see citing works
A Pore Idea: the ion conduction pathway of TMEM16/ANO proteins is composed partly of lipid
Whitlock, J. M., & Hartzell, H. C. (2016) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-015-1777-2 · Cited by 67 · see citing works
Duriseti, S., Goetz, D. H., Hostetter, D. R., LeBeau, A. M., Wei, Y., & Craik, C. S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.077677 · Cited by 61 · see citing works
Self-citationScudieri, P., Sondo, E., Caci, E., Ravazzolo, R., & Galietta, L. J. V. (2013) · Biochemical Journal · doi:10.1042/bj20130348 · Cited by 39 · see citing works
Intermolecular Interactions in the TMEM16A Dimer Controlling Channel Activity
Scudieri, P., Musante, I., Gianotti, A., Morán, Ó., & Galietta, L. J. V. (2016) · Scientific Reports · doi:10.1038/srep38788 · Cited by 15 · see citing works
Nanodisc-Tm: Rapid functional assessment of nanodisc reconstituted membrane proteins by CPM assay
Ashok, Y., & Jaakola, V. (2016) · MethodsX · doi:10.1016/j.mex.2016.03.009 · Cited by 9 · see citing works
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Challenges and opportunities in cryo-EM single-particle analysis
Lyumkis, D. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.rev118.005602 · Cited by 362 · see citing works
TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells
Pan, B., Akyuz, N., Liu, X.-P., Asai, Y., Nist-Lund, C. A., Kurima, K., Derfler, B. H., György, B., Limapichat, W., Walujkar, S., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.07.033 · Cited by 357 · see citing works
Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms
Billesbølle, C. B., Azumaya, C. M., Kretsch, R. C., Powers, A. S., Gonen, S., Schneider, S., Arvedson, T., Dror, R. O., Cheng, Y., & Manglik, A. (2020) · Nature · doi:10.1038/s41586-020-2668-z · Cited by 344 · see citing works
Self-citationCryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs
Kern, D. M., Sorum, B., Mali, S. S., Hoel, C., Sridharan, S., Remis, J. P., Toso, D. B., Kotecha, A., Bautista, D. M., & Brohawn, S. G. (2021) · Nature Structural & Molecular Biology · doi:10.1038/s41594-021-00619-0 · Cited by 316 · see citing works
Mechanosensitive Ion Channels: Structural Features Relevant to Mechanotransduction Mechanisms
Jin, P., Jan, L. Y., & Jan, Y. N. (2020) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-070918-050509 · Cited by 276 · see citing works
Self-citationStructural basis of odorant recognition by a human odorant receptor
Billesbølle, C. B., de March, C. A., van der Velden, W. J. C., Ma, N., Tewari, J., del Torrent, C. L., Li, L., Faust, B., Vaidehi, N., Matsunami, H., et al. (2023) · Nature · doi:10.1038/s41586-023-05798-y · Cited by 245 · see citing works
Structural snapshots of TRPV1 reveal mechanism of polymodal functionality
Zhang, K., Julius, D. J., & Cheng, Y. (2021) · Cell · doi:10.1016/j.cell.2021.08.012 · Cited by 230 · see citing works
Self-citationStructure of the mechanosensitive OSCA channels
Zhang, M., Wang, D., Kang, Y., Wu, J.-X., Yao, F., Pan, C., Yan, Z., Song, C., & Chen, L. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0117-6 · Cited by 215 · see citing works
Irritant-evoked activation and calcium modulation of the TRPA1 receptor
Zhao, J., King, J. V. L., Paulsen, C. E., Cheng, Y., & Julius, D. J. (2020) · Nature · doi:10.1038/s41586-020-2480-9 · Cited by 198 · see citing works
Self-citationStructure of the hyperosmolality-gated calcium-permeable channel OSCA1.2
Liu, X., Wang, J., & Sun, L. (2018) · Nature Communications · doi:10.1038/s41467-018-07564-5 · Cited by 179 · see citing works
The roles of calcium and ATP in the physiology and pathology of the exocrine pancreas
Petersen, O. H., Gerasimenko, J. V., Gerasimenko, O. V., Gryshchenko, O., & Peng, S. (2021) · Physiological Reviews · doi:10.1152/physrev.00003.2021 · Cited by 176 · see citing works
Cryo-EM structure of the mechanically activated ion channel OSCA1.2
Jojoa-Cruz, S., Saotome, K., Murthy, S. E., Tsui, C. C., Sansom, M. S. P., Patapoutian, A., & Ward, A. B. (2018) · eLife · doi:10.7554/elife.41845 · Cited by 176 · see citing works
Bushell, S. R., Pike, A. C. W., Falzone, M. E., Rorsman, N. J. G., Ta, C. M., Corey, R. A., Newport, T. D., Christianson, J. C., Scofano, L. F., Shintre, C. A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11753-1 · Cited by 157 · see citing works
Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F
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Structures of the TMC-1 complex illuminate mechanosensory transduction
Jeong, H., Clark, S., Goehring, A. S., Dehghani‐Ghahnaviyeh, S., Rasouli, A., Tajkhorshid, E., & Gouaux, E. (2022) · Nature · doi:10.1038/s41586-022-05314-8 · Cited by 151 · see citing works
Marx, S., Maso, T. D., Chen, J.-W., Bury, M., Wouters, J., Michiels, C., & Calvé, B. L. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.08.018 · Cited by 147 · see citing works
Uchański, T., Masiulis, S., Fischer, B., Kalichuk, V., López-Sánchez, U., Zarkadas, E., Weckener, M., Sente, A., Ward, P. N., Wohlkönig, A., et al. (2021) · Nature Methods · doi:10.1038/s41592-020-01001-6 · Cited by 147 · see citing works
Cryo-EM analysis of a membrane protein embedded in the liposome
Yao, X. Y., Fan, X., & Yan, N. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2009385117 · Cited by 143 · see citing works
Korte, N., Ilkan, Z., Pearson, C. L., Pfeiffer, T., Singhal, P., Rock, J., Sethi, H., Gill, D., Attwell, D., & Tammaro, P. (2022) · Journal of Clinical Investigation · doi:10.1172/jci154118 · Cited by 132 · see citing works
Maity, K., Heumann, J. M., McGrath, A. P., Kopcho, N. J., Hsu, P., Lee, C., Mapes, J., Garza, D., Krishnan, S., Morgan, G., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1900774116 · Cited by 125 · see citing works
Miner, K. T., Labitzke, K., Liu, B., Wang, P., Henckels, K., Gaida, K., Elliott, R., Chen, J. J., Liu, L., Leith, A., et al. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00051 · Cited by 124 · see citing works
Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase
Falzone, M. E., Rheinberger, J., Lee, B., Peyear, T. A., Sasset, L., Raczkowski, A. M., Eng, E. T., Lorenzo, A. D., Andersen, O. S., Nimigean, C. M., et al. (2019) · eLife · doi:10.7554/elife.43229 · Cited by 122 · see citing works
Ballesteros, Á., Fenollar‐Ferrer, C., & Swartz, K. J. (2018) · eLife · doi:10.7554/elife.38433 · Cited by 120 · see citing works
The multifaceted role of TMEM16A in cancer
Crottès, D., & Jan, L. Y. (2019) · Cell Calcium · doi:10.1016/j.ceca.2019.06.004 · Cited by 118 · see citing works
Self-citationRecent advances in TMEM16A: Structure, function, and disease
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Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs
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Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM
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Known structures and unknown mechanisms of TMEM16 scramblases and channels
Falzone, M. E., Malvezzi, M., Lee, B.-C., & Accardi, A. (2018) · The Journal of General Physiology · doi:10.1085/jgp.201711957 · Cited by 112 · see citing works
Feng, S., Dang, S., Han, T. W., Ye, W., Jin, P., Cheng, T., Li, J., Jan, Y. N., Jan, L. Y., & Cheng, Y. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.023 · Cited by 112 · see citing works
Self-citationStructural basis for catalysis and substrate specificity of human ACAT1
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Single-particle cryo-EM structure of a voltage-activated potassium channel in lipid nanodiscs
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Structure of atOSCA3.1 channel
Chen, L., Zhang, M., Kang, Y., & Wu, J.-X. (2017) · Worldwide Protein Data Bank · doi:10.2210/pdb5z1f/pdb · Cited by 106 · see citing works
Flagging fusion: Phosphatidylserine signaling in cell–cell fusion
Whitlock, J. M., & Chernomordik, L. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100411 · Cited by 101 · see citing works
Molecular basis of PIP2-dependent regulation of the Ca2+-activated chloride channel TMEM16A
Le, S. C., Jia, Z., Chen, J., & Yang, H. (2019) · Nature Communications · doi:10.1038/s41467-019-11784-8 · Cited by 99 · see citing works
The Groovy TMEM16 Family: Molecular Mechanisms of Lipid Scrambling and Ion Conduction
Kalienkova, V., Mosina, V. C., & Paulino, C. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.166941 · Cited by 99 · see citing works
Structure-based discovery of conformationally selective inhibitors of the serotonin transporter
Singh, I., Seth, A., Billesbølle, C. B., Bráz, J. M., Rodriguiz, R. M., Roy, K., Bekele, B., Craik, V., Huang, X., Boytsov, D., et al. (2023) · Cell · doi:10.1016/j.cell.2023.04.010 · Cited by 99 · see citing works
Structure of mechanically activated ion channel OSCA1.2 in nanodisc
Jojoa-Cruz, S., Saotome, K., Patapoutian, A., & Ward, A. B. (2018) · Worldwide Protein Data Bank · doi:10.2210/pdb6mgv/pdb · Cited by 97 · see citing works
Selective G protein signaling driven by substance P–neurokinin receptor dynamics
Harris, J. A., Faust, B., Gondin, A. B., Dämgen, M. A., Suomivuori, C., Veldhuis, N. A., Cheng, Y., Dror, R. O., Thal, D. M., & Manglik, A. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00890-8 · Cited by 97 · see citing works
Self-citationGating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase
Lee, B., Khelashvili, G., Falzone, M. E., Menon, A. K., Weinstein, H., & Accardi, A. (2018) · Nature Communications · doi:10.1038/s41467-018-05724-1 · Cited by 93 · see citing works
Structural basis for inhibition of the drug efflux pump NorA from Staphylococcus aureus
Brawley, D. N., Sauer, D. B., Li, J., Zheng, X., Koide, A., Jedhe, G. S., Suwatthee, T., Song, J., Liu, Z., Arora, P. S., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-00994-9 · Cited by 93 · see citing works
Peters, C. J., Gilchrist, J. M., Tien, J., Bethel, N. P., Qi, L., Chen, T., Wang, L., Jan, Y. N., Grabe, M., & Jan, L. Y. (2018) · Neuron · doi:10.1016/j.neuron.2018.01.048 · Cited by 91 · see citing works
Self-citationAn inner activation gate controls TMEM16F phospholipid scrambling
Le, T., Jia, Z., Le, S. C., Zhang, Y., Chen, J., & Yang, H. (2019) · Nature Communications · doi:10.1038/s41467-019-09778-7 · Cited by 91 · see citing works
Membrane mimetic systems in CryoEM: keeping membrane proteins in their native environment
Autzen, H. E., Julius, D. J., & Cheng, Y. (2019) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2019.05.022 · Cited by 91 · see citing works
Self-citationFusion protein strategies for cryo-EM study of G protein-coupled receptors
Zhang, K., Wu, H., Hoppe, N., Manglik, A., & Cheng, Y. (2022) · Nature Communications · doi:10.1038/s41467-022-32125-2 · Cited by 91 · see citing works
Self-citationTMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels
Wang, Z., Rawson, S. D., Shen, Z., Tamilselvan, E., Smith, H. E., Halford, J., Shen, C., Murthy, S. E., Ulbrich, M. H., Sotomayor, M. M., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.07.006 · Cited by 89 · see citing works
Single-molecule analysis of phospholipid scrambling by TMEM16F
Watanabe, R., Sakuragi, T., Noji, H., & Nagata, S. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1717956115 · Cited by 89 · see citing works
Jha, A., Chung, W. Y., Vachel, L., Maléth, J., Lake, S., Zhang, G., Ahuja, M., & Muallem, S. (2019) · The EMBO Journal · doi:10.15252/embj.2018101452 · Cited by 87 · see citing works
Why recombinant antibodies — benefits and applications
Basu, K., Green, E. M., Cheng, Y., & Craik, C. S. (2019) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2019.01.012 · Cited by 86 · see citing works
Self-citationStructure and inhibition mechanism of the human citrate transporter NaCT
Sauer, D. B., Song, J., Wang, B., Hilton, J. K., Karpowich, N. K., Mindell, J. A., Rice, W. J., & Wang, D. (2021) · Nature · doi:10.1038/s41586-021-03230-x · Cited by 82 · see citing works
Liu, Y., Liu, Z., & Wang, K. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.12.003 · Cited by 80 · see citing works
Yu, K., Jiang, T., Cui, Y., Tajkhorshid, E., & Hartzell, H. C. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1904012116 · Cited by 74 · see citing works
TMEM16A controls EGF-induced calcium signaling implicated in pancreatic cancer prognosis
Crottès, D., Lin, Y.-H. T., Peters, C. J., Gilchrist, J. M., Wiita, A. P., Jan, Y. N., & Jan, L. Y. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1900703116 · Cited by 75 · see citing works
Self-citationThe human pre-replication complex is an open complex.
Li, J. Y., Dong, J., Wang, W., Yu, D.-Q., Fan, X., Hui, Y., Lee, C. S. K., Lam, W.-H., Alary, N., Yang, Y., et al. (2023) · Cell · doi:10.1016/j.cell.2022.12.008 · Cited by 71 · see citing works
Self-citationA mechanical-coupling mechanism in OSCA/TMEM63 channel mechanosensitivity
Zhang, M., Shan, Y., Cox, C. D., & Pei, D. (2023) · Nature Communications · doi:10.1038/s41467-023-39688-8 · Cited by 75 · see citing works
Gating of human TRPV3 in a lipid bilayer
Deng, Z., Maksaev, G. I., Rau, M., Xie, Z., Hu, H., Fitzpatrick, J. A. J., & Yuan, P. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-0428-2 · Cited by 75 · see citing works
Out-of-the-groove transport of lipids by TMEM16 and GPCR scramblases
Malvezzi, M., Andra, K. K., Pandey, K., Lee, B., Falzone, M. E., Brown, A., Iqbal, R., Menon, A. K., & Accardi, A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1806721115 · Cited by 74 · see citing works
Menin “reads” H3K79me2 mark in a nucleosomal context
Lin, J., Wu, Y., Tian, G., Yu, D., Yang, E., Lam, W. H., Liu, Z., Jing, Y., Dang, S., Bao, X., et al. (2023) · Science · doi:10.1126/science.adc9318 · Cited by 71 · see citing works
Self-citationNon-uniformity of projection distributions attenuates resolution in Cryo-EM
Baldwin, P. R., & Lyumkis, D. (2019) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2019.09.002 · Cited by 68 · see citing works
Rational ion transport management mediated through membrane structures
Chen, Y., Zhu, Z., Tian, Y. F., & Jiang, L. (2021) · Exploration · doi:10.1002/exp.20210101 · Cited by 68 · see citing works
Function and Dysfunction of TMC Channels in Inner Ear Hair CellsPreprint
Corey, D. P., Akyuz, N., & Holt, J. R. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a033506 · Cited by 66 · see citing works
TMEM16 scramblases thin the membrane to enable lipid scrambling
Falzone, M. E., Feng, Z., Alvarenga, O. E., Pan, Y., Lee, B., Cheng, X., Fortea, E., Simon Scheuring, A., & Accardi, A. (2022) · Nature Communications · doi:10.1038/s41467-022-30300-z · Cited by 65 · see citing works
Ye, W., Han, T. W., Nassar, L. M., Zubia, M. V., Jan, Y. N., & Jan, L. Y. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1718728115 · Cited by 64 · see citing works
Self-citationTembo, M., Wozniak, K. L., Bainbridge, R. E., & Carlson, A. E. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.007128 · Cited by 64 · see citing works
The role of π-helices in TRP channel gating
Zubcevic, L., & Lee, S. (2019) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2019.06.011 · Cited by 64 · see citing works
Rheinberger, J., Gao, X., Schmidpeter, P. A. M., & Nimigean, C. M. (2018) · eLife · doi:10.7554/elife.39775 · Cited by 63 · see citing works
Structure of the rice hyperosmolality-gated ion channel OSCA1.2
Maity, K., Heumann, J. M., McGrath, A. P., Chang, G. A., & Stowell, M. H. B. (2019) · Worldwide Protein Data Bank · doi:10.2210/pdb6oce/pdb · Cited by 63 · see citing works
The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes
Hariharan, A., Weir, N., Robertson, C., He, L., Betsholtz, C., & Longden, T. A. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.601324 · Cited by 63 · see citing works
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Tonggu, L., & Wang, L. (2019) · Ultramicroscopy · doi:10.1016/j.ultramic.2019.112849 · Cited by 62 · see citing works
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Wang, J., Yu, X., Ding, Z. J., Zhang, X., Luo, Y., Xu, X., Xie, Y., Li, X., Yuan, T., Zheng, S. J., et al. (2021) · Cell Research · doi:10.1038/s41422-021-00587-6 · Cited by 60 · see citing works
Current outcomes when optimizing ‘standard’ sample preparation for single‐particle cryo‐EM
Carragher, B. O., Cheng, Y., Frost, A. S., Glaeser, R. M., Lander, G. C., Nogales, E., & WANG, H. ‐. (2019) · Journal of Microscopy · doi:10.1111/jmi.12834 · Cited by 60 · see citing works
Self-citationNociceptor Signalling through ion Channel Regulation via GPCRs
Salzer, I., Ray, S., Schicker, K. W., & Boehm, S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20102488 · Cited by 59 · see citing works
Gating the pore of the calcium-activated chloride channel TMEM16A
Lam, A. K. M., Rheinberger, J., Paulino, C., & Dutzler, R. (2021) · Nature Communications · doi:10.1038/s41467-020-20787-9 · Cited by 56 · see citing works
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Arndt, M., Alvadia, C., Straub, M. S., Mosina, V. C., Paulino, C., & Dutzler, R. (2022) · Nature Communications · doi:10.1038/s41467-022-34497-x · Cited by 55 · see citing works
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Takayama, Y., Derouiche, S., Maruyama, K., & Tominaga, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20143411 · Cited by 54 · see citing works
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Ousingsawat, J., Schreiber, R., & Kunzelmann, K. (2019) · Cancers · doi:10.3390/cancers11050625 · Cited by 52 · see citing works
Reorientation of INO80 on hexasomes reveals basis for mechanistic versatility
Wu, H., Muñoz, E. N., Hsieh, L. J., Chio, U. S., Gourdet, M. A., Narlikar, G. J., & Cheng, Y. (2023) · Science · doi:10.1126/science.adf4197 · Cited by 50 · see citing works
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de March, C. A., Ma, N., Billesbølle, C. B., Tewari, J., del Torrent, C. L., van der Velden, W. J. C., Ojiro, I., Takayama, I., Faust, B., Li, L., et al. (2024) · Nature · doi:10.1038/s41586-024-08126-0 · Cited by 55 · see citing works
Lam, A. K. M., & Dutzler, R. (2018) · eLife · doi:10.7554/elife.39122 · Cited by 48 · see citing works
Chemically induced vesiculation as a platform for studying TMEM16F activity
Han, T. W., Ye, W., Bethel, N. P., Zubia, M. V., Kim, A., Li, K. H., Burlingame, A. L., Grabe, M., Jan, Y. N., & Jan, L. Y. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1817498116 · Cited by 47 · see citing works
Self-citationFeng, S., Puchades, C., Ko, J., Wu, H., Chen, Y., Figueroa, E. E., Gu, S., Han, T. W., Ho, B., Cheng, T., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40410-x · Cited by 46 · see citing works
Self-citationCryo-EM structure of a proton-activated chloride channel TMEM206
Deng, Z., Zhao, Y., Feng, J., Zhang, J., Zhao, H., Rau, M., Fitzpatrick, J. A. J., Hu, H., & Yuan, P. (2021) · Science Advances · doi:10.1126/sciadv.abe5983 · Cited by 46 · see citing works
Molecular mechanisms of activation and regulation of ANO1-Encoded Ca 2+ -Activated Cl - channels
Hawn, M. B., Akin, E. J., Hartzell, H. C., Greenwood, I. A., & Leblanc, N. (2021) · Channels · doi:10.1080/19336950.2021.1975411 · Cited by 46 · see citing works
Drug development in targeting ion channels for brain edema
Luo, Z., Ovcjak, A., Wong, R., Yang, B., Feng, Z., & Sun, H. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00503-5 · Cited by 45 · see citing works
Assemblies of lauryl maltose neopentyl glycol (LMNG) and LMNG-solubilized membrane proteins
Breyton, C., Javed, W., Vermot, A., Arnaud, C., Hajjar, C., Dupuy, J., Petit-Härtlein, I., Roy, A. L., Martel, A., Thépaut, M., et al. (2019) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2019.02.003 · Cited by 45 · see citing works
The ϕPA3 phage nucleus is enclosed by a self-assembling 2D crystalline lattice
(2023) · doi:10.1038/s41467-023-36526-9 · Cited by 45 · see citing works
Self-citationPhysiology of Electrolyte Transport in the Gut: Implications for Disease
Rao, M. C. (2019) · Comprehensive physiology · doi:10.1002/cphy.c180011 · Cited by 53 · see citing works
Molecular goniometers for single-particle cryo-electron microscopy of DNA-binding proteins
Aksel, T., Yu, Z., Cheng, Y., & Douglas, S. M. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0716-8 · Cited by 44 · see citing works
Self-citationMechanism of pore opening in the calcium-activated chloride channel TMEM16A
Lam, A. K. M., & Dutzler, R. (2021) · Nature Communications · doi:10.1038/s41467-020-20788-8 · Cited by 44 · see citing works
Specific PIP2 binding promotes calcium activation of TMEM16A chloride channels
Jia, Z., & Chen, J. (2021) · Communications Biology · doi:10.1038/s42003-021-01782-2 · Cited by 44 · see citing works
Sun, W., Guo, S., Li, Y., Li, J., Liu, C., Chen, Y., Wang, X., Tian, H., Tian, H., Wang, C., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30625-9 · Cited by 43 · see citing works
Quesada, R., & Dutzler, R. (2019) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2019.10.020 · Cited by 42 · see citing works
Role of oxygen and the HIF-pathway in polycystic kidney disease
Buchholz, B., & Eckardt, K. (2020) · Cellular Signalling · doi:10.1016/j.cellsig.2020.109524 · Cited by 42 · see citing works
Kang, H., & Lee, C. J. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01206-1 · Cited by 40 · see citing works
An Additional Ca2+ Binding Site Allosterically Controls TMEM16A Activation
Le, S. C., & Yang, H. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108570 · Cited by 41 · see citing works
The pharmacology of the TMEM16A channel: therapeutic opportunities
Al‐Hosni, R., Ilkan, Z., Agostinelli, E., & Tammaro, P. (2022) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2022.06.006 · Cited by 40 · see citing works
Calcium-Activated Chloride Channel ANO1/TMEM16A: Regulation of Expression and Signaling
Dulin, N. O. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.590262 · Cited by 39 · see citing works
The cyclic AMP signaling pathway in the rodent main olfactory system
Boccaccio, A., Menini, A., & Pifferi, S. (2021) · Cell and Tissue Research · doi:10.1007/s00441-020-03391-7 · Cited by 39 · see citing works
Bon, C. L., Michon, B., Popot, J., & Zoonens, M. A. (2021) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583521000044 · Cited by 39 · see citing works
- Authors
- Dang, S., Feng, S., Tien, J., Peters, C. J., Bulkley, D., Lolicato, M., Zhao, J., Zuberbühler, K., Ye, W., Qi, L., Chen, T., Craik, C. S., Jan, Y. N., Minor, D. L., Cheng, Y., & Jan, L. Y.
- Affiliations
- University of California, San Francisco (US)
- Howard Hughes Medical Institute (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Cheng, Yifan
- Jan, Lily Yeh
- ORCID
- Venue
- Nature
- Published
- 2017-12
- Volume
- 552
- Issue
- 7685
- Pages
- 426-429
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5750132
- OpenAlex
- W2774013165
- Cited by
- 333
- References
- 54
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 32 · 2023: 28 · 2022: 38 · 2021: 54 · 2020: 40 · 2019: 64 · 2018: 29 · 2015: 1
- FWCI
- 15.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1s10od020054-01)
- National Heart, Lung, and Blood Institute (R01HL080050)
- National Institute on Drug Abuse (K99DA041500)
- National Cancer Institute (P41CA196276)
- National Institute on Deafness and Other Communication Disorders (R01DC007664)
- National Institute of General Medical Sciences (P50GM082250, P01GM111126, R01GM098672)
- National Institute of Neurological Disorders and Stroke (R01NS069229, R35NS097227)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Keywords
- TMEM16A, calcium-activated chloride channels, TMEM16, channel gating, calcium binding, channel rundown, nanodiscs, detergent solubilization, pore-lining residues, lipid scramblase, channel structure-function relationship
- MeSH terms
- Anoctamin-1, Animals, Anions, Calcium, Glucosides, Humans, Models, Molecular, Protein Conformation, Ion Channel Gating, Ion Transport, Cryoelectron Microscopy, Nanostructures, Mice, HEK293 Cells
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