4wit › Citations

X-ray structure of a calcium-activated TMEM16 lipid scramblase.

Brunner JD, Lim NK, Schenck S, Duerst A, Dutzler R
Nature 516 207-12 (2014)
Cited: 268 times
EuropePMC logo PMID: 25383531

Abstract

The TMEM16 family of proteins, also known as anoctamins, features a remarkable functional diversity. This family contains the long sought-after Ca(2+)-activated chloride channels as well as lipid scramblases and cation channels. Here we present the crystal structure of a TMEM16 family member from the fungus Nectria haematococca that operates as a Ca(2+)-activated lipid scramblase. Each subunit of the homodimeric protein contains ten transmembrane helices and a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbours a conserved Ca(2+)-binding site located within the hydrophobic core of the membrane. Mutations of residues involved in Ca(2+) coordination affect both lipid scrambling in N. haematococca TMEM16 and ion conduction in the Cl(-) channel TMEM16A. The structure reveals the general architecture of the family and its mode of Ca(2+) activation. It also provides insight into potential scrambling mechanisms and serves as a framework to unravel the conduction of ions in certain TMEM16 proteins.

Reviews - 4wit mentioned but not cited (3)

  1. Decoding P4-ATPase substrate interactions. Roland BP, Graham TR. Crit Rev Biochem Mol Biol 51 513-527 (2016)
  2. Sticking With It: ER-PM Membrane Contact Sites as a Coordinating Nexus for Regulating Lipids and Proteins at the Cell Cortex. Zaman MF, Nenadic A, Radojičić A, Rosado A, Beh CT. Front Cell Dev Biol 8 675 (2020)
  3. Transport Pathways That Contribute to the Cellular Distribution of Phosphatidylserine. Lenoir G, D'Ambrosio JM, Dieudonné T, Čopič A. Front Cell Dev Biol 9 737907 (2021)

Articles - 4wit mentioned but not cited (7)



Reviews citing this publication (74)

  1. Apoptosis and Clearance of Apoptotic Cells. Nagata S. Annu Rev Immunol 36 489-517 (2018)
  2. An Apoptotic 'Eat Me' Signal: Phosphatidylserine Exposure. Segawa K, Nagata S. Trends Cell Biol 25 639-650 (2015)
  3. Getting to the Outer Leaflet: Physiology of Phosphatidylserine Exposure at the Plasma Membrane. Bevers EM, Williamson PL. Physiol Rev 96 605-645 (2016)
  4. Exposure of phosphatidylserine on the cell surface. Nagata S, Suzuki J, Segawa K, Fujii T. Cell Death Differ 23 952-961 (2016)
  5. P4-ATPases as Phospholipid Flippases-Structure, Function, and Enigmas. Andersen JP, Vestergaard AL, Mikkelsen SA, Mogensen LS, Chalat M, Molday RS. Front Physiol 7 275 (2016)
  6. Emerging Diversity in Lipid-Protein Interactions. Corradi V, Sejdiu BI, Mesa-Galloso H, Abdizadeh H, Noskov SY, Marrink SJ, Tieleman DP. Chem Rev 119 5775-5848 (2019)
  7. Anoctamins/TMEM16 Proteins: Chloride Channels Flirting with Lipids and Extracellular Vesicles. Whitlock JM, Hartzell HC. Annu Rev Physiol 79 119-143 (2017)
  8. Lipid somersaults: Uncovering the mechanisms of protein-mediated lipid flipping. Pomorski TG, Menon AK. Prog Lipid Res 64 69-84 (2016)
  9. Cellular functions of TMEM16/anoctamin. Oh U, Jung J. Pflugers Arch 468 443-453 (2016)
  10. Targeting ion channels in cystic fibrosis. Mall MA, Galietta LJ. J Cyst Fibros 14 561-570 (2015)
  11. Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer. Wang H, Zou L, Ma K, Yu J, Wu H, Wei M, Xiao Q. Mol Cancer 16 152 (2017)
  12. Aminoglycoside- and Cisplatin-Induced Ototoxicity: Mechanisms and Otoprotective Strategies. Kros CJ, Steyger PS. Cold Spring Harb Perspect Med 9 a033548 (2019)
  13. Known structures and unknown mechanisms of TMEM16 scramblases and channels. Falzone ME, Malvezzi M, Lee BC, Lee BC, Accardi A. J Gen Physiol 150 933-947 (2018)
  14. Phosphatidylserine Is the Signal for TAM Receptors and Their Ligands. Lemke G. Trends Biochem Sci 42 738-748 (2017)
  15. Roles and regulation of phospholipid scramblases. Kodigepalli KM, Bowers K, Sharp A, Nanjundan M. FEBS Lett 589 3-14 (2015)
  16. Lipids at membrane contact sites: cell signaling and ion transport. Muallem S, Chung WY, Jha A, Ahuja M. EMBO Rep 18 1893-1904 (2017)
  17. A Pore Idea: the ion conduction pathway of TMEM16/ANO proteins is composed partly of lipid. Whitlock JM, Hartzell HC. Pflugers Arch 468 455-473 (2016)
  18. Structural basis for phospholipid scrambling in the TMEM16 family. Brunner JD, Schenck S, Dutzler R. Curr Opin Struct Biol 39 61-70 (2016)
  19. Recent advances in TMEM16A: Structure, function, and disease. Ji Q, Guo S, Wang X, Pang C, Zhan Y, Chen Y, An H. J Cell Physiol 234 7856-7873 (2019)
  20. Flagging fusion: Phosphatidylserine signaling in cell-cell fusion. Whitlock JM, Chernomordik LV. J Biol Chem 296 100411 (2021)
  21. Ion channels in regulated cell death. Kunzelmann K. Cell Mol Life Sci 73 2387-2403 (2016)
  22. Contribution of Anoctamins to Cell Survival and Cell Death. Kunzelmann K, Ousingsawat J, Benedetto R, Cabrita I, Schreiber R. Cancers (Basel) 11 E382 (2019)
  23. Biogenesis, transport and remodeling of lysophospholipids in Gram-negative bacteria. Zheng L, Lin Y, Lu S, Zhang J, Bogdanov M. Biochim Biophys Acta Mol Cell Biol Lipids 1862 1404-1413 (2017)
  24. Modulating Ca²⁺ signals: a common theme for TMEM16, Ist2, and TMC. Kunzelmann K, Cabrita I, Wanitchakool P, Ousingsawat J, Sirianant L, Benedetto R, Schreiber R. Pflugers Arch 468 475-490 (2016)
  25. TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca(2+) and cell volume. Kunzelmann K. Trends Biochem Sci 40 535-543 (2015)
  26. Recent applications of light scattering measurement in the biological and biopharmaceutical sciences. Minton AP. Anal Biochem 501 4-22 (2016)
  27. The ER/PM microdomain, PI(4,5)P₂ and the regulation of STIM1-Orai1 channel function. Cao X, Choi S, Maléth JJ, Park S, Ahuja M, Muallem S. Cell Calcium 58 342-348 (2015)
  28. Phospholipid scrambling by rhodopsin. Ernst OP, Menon AK. Photochem Photobiol Sci 14 1922-1931 (2015)
  29. Structure and Function of Ion Channels Regulating Sperm Motility-An Overview. Nowicka-Bauer K, Szymczak-Cendlak M. Int J Mol Sci 22 3259 (2021)
  30. The long tale of the calcium activated Cl- channels in olfactory transduction. Dibattista M, Pifferi S, Boccaccio A, Menini A, Reisert J. Channels (Austin) 11 399-414 (2017)
  31. Emerging Perspectives on Pain Management by Modulation of TRP Channels and ANO1. Takayama Y, Derouiche S, Maruyama K, Tominaga M. Int J Mol Sci 20 E3411 (2019)
  32. The Mechanosensory Transduction Machinery in Inner Ear Hair Cells. Zheng W, Holt JR. Annu Rev Biophys 50 31-51 (2021)
  33. Function and Dysfunction of TMC Channels in Inner Ear Hair Cells. Corey DP, Akyuz N, Holt JR. Cold Spring Harb Perspect Med 9 a033506 (2019)
  34. Phospholipid Scramblases. Williamson P. Lipid Insights 8 41-44 (2015)
  35. Lipid Exchangers: Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism. Lipp NF, Ikhlef S, Milanini J, Drin G. Front Cell Dev Biol 8 663 (2020)
  36. Novel Roles for Chloride Channels, Exchangers, and Regulators in Chronic Inflammatory Airway Diseases. Sala-Rabanal M, Yurtsever Z, Berry KN, Brett TJ. Mediators Inflamm 2015 497387 (2015)
  37. Ca2+ influx at the ER/PM junctions. Chung WY, Jha A, Ahuja M, Muallem S. Cell Calcium 63 29-32 (2017)
  38. Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases. Sakuragi T, Nagata S. Nat Rev Mol Cell Biol 24 576-596 (2023)
  39. Continuum descriptions of membranes and their interaction with proteins: Towards chemically accurate models. Argudo D, Bethel NP, Marcoline FV, Grabe M. Biochim Biophys Acta 1858 1619-1634 (2016)
  40. The Ca2+-activated chloride channel ANO1/TMEM16A: An emerging therapeutic target for epithelium-originated diseases? Liu Y, Liu Z, Wang K. Acta Pharm Sin B 11 1412-1433 (2021)
  41. The synthesis of recombinant membrane proteins in yeast for structural studies. Routledge SJ, Mikaliunaite L, Patel A, Clare M, Cartwright SP, Bawa Z, Wilks MD, Low F, Hardy D, Rothnie AJ, Bill RM. Methods 95 26-37 (2016)
  42. Lipid topogenesis--35years on. Chauhan N, Farine L, Pandey K, Menon AK, Bütikofer P. Biochim Biophys Acta 1861 757-766 (2016)
  43. Nociceptor Signalling through ion Channel Regulation via GPCRs. Salzer I, Ray S, Schicker K, Boehm S. Int J Mol Sci 20 E2488 (2019)
  44. Phospholipid Scrambling by G Protein-Coupled Receptors. Khelashvili G, Menon AK. Annu Rev Biophys 51 39-61 (2022)
  45. Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes. Manna M, Nieminen T, Vattulainen I. Annu Rev Biophys 48 421-439 (2019)
  46. Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies. Croissant C, Carmeille R, Brévart C, Bouter A. Int J Mol Sci 22 5276 (2021)
  47. Calmodulin regulation of TMEM16A and 16B Ca(2+)-activated chloride channels. Yang T, Colecraft HM. Channels (Austin) 10 38-44 (2016)
  48. NBD-based synthetic probes for sensing small molecules and proteins: design, sensing mechanisms and biological applications. Jiang C, Huang H, Kang X, Yang L, Xi Z, Sun H, Pluth MD, Yi L. Chem Soc Rev 50 7436-7495 (2021)
  49. Advances and challenges of membrane-protein complex production. Zorman S, Botte M, Jiang Q, Collinson I, Schaffitzel C. Curr Opin Struct Biol 32 123-130 (2015)
  50. CLCA1 and TMEM16A: the link towards a potential cure for airway diseases. Brett TJ. Expert Rev Respir Med 9 503-506 (2015)
  51. New Insights on the Regulation of Ca2+ -Activated Chloride Channel TMEM16A. Ma K, Wang H, Yu J, Wei M, Xiao Q. J Cell Physiol 232 707-716 (2017)
  52. Orai1 and STIM1 in ER/PM junctions: roles in pancreatic cell function and dysfunction. Son A, Park S, Shin DM, Muallem S. Am J Physiol Cell Physiol 310 C414-22 (2016)
  53. Molecular mechanisms of activation and regulation of ANO1-Encoded Ca2+-Activated Cl- channels. Hawn MB, Akin E, Hartzell HC, Greenwood IA, Leblanc N. Channels (Austin) 15 569-603 (2021)
  54. The cyclic AMP signaling pathway in the rodent main olfactory system. Boccaccio A, Menini A, Pifferi S. Cell Tissue Res 383 429-443 (2021)
  55. Recent progress in structural studies on TMEM16A channel. Shi S, Pang C, Guo S, Chen Y, Ma B, Qu C, Ji Q, An H. Comput Struct Biotechnol J 18 714-722 (2020)
  56. Mechanisms of Non-Vesicular Exchange of Lipids at Membrane Contact Sites: Of Shuttles, Tunnels and, Funnels. Egea PF. Front Cell Dev Biol 9 784367 (2021)
  57. Role of lipid transporters in fungal physiology and pathogenicity. Rizzo J, Stanchev LD, da Silva VKA, Nimrichter L, Pomorski TG, Rodrigues ML. Comput Struct Biotechnol J 17 1278-1289 (2019)
  58. The diverse roles of TMEM16A Ca2+-activated Cl- channels in inflammation. Bai W, Liu M, Xiao Q. J Adv Res 33 53-68 (2021)
  59. Endoplasmic Reticulum-Plasma Membrane Contact Sites as an Organizing Principle for Compartmentalized Calcium and cAMP Signaling. Crul T, Maléth J. Int J Mol Sci 22 4703 (2021)
  60. Gating and Regulatory Mechanisms of TMEM16 Ion Channels and Scramblases. Le SC, Liang P, Lowry AJ, Yang H. Front Physiol 12 787773 (2021)
  61. Putting the Pieces Together: the Hair Cell Transduction Complex. Holt JR, Tobin M, Elferich J, Gouaux E, Ballesteros A, Yan Z, Ahmed ZM, Nicolson T. J Assoc Res Otolaryngol 22 601-608 (2021)
  62. Calcium-Activated Chloride Channels in Myometrial and Vascular Smooth Muscle. Wray S, Prendergast C, Arrowsmith S. Front Physiol 12 751008 (2021)
  63. Calcium-Activated Cl- Channel: Insights on the Molecular Identity in Epithelial Tissues. Rottgen TS, Nickerson AJ, Rajendran VM. Int J Mol Sci 19 E1432 (2018)
  64. Emerging Modulators of TMEM16A and Their Therapeutic Potential. Hao A, Guo S, Shi S, Wang X, Zhan Y, Chen Y, An H. J Membr Biol 254 353-365 (2021)
  65. Polymodal Control of TMEM16x Channels and Scramblases. Agostinelli E, Tammaro P. Int J Mol Sci 23 1580 (2022)
  66. TMEM16A/ANO1: Current Strategies and Novel Drug Approaches for Cystic Fibrosis. Mitri C, Sharma H, Corvol H, Tabary O. Cells 10 2867 (2021)
  67. ANO10 Function in Health and Disease. Chrysanthou A, Ververis A, Christodoulou K. Cerebellum 22 447-467 (2023)
  68. Mechanosensitive Ion Channels, Axonal Growth, and Regeneration. Miles L, Powell J, Kozak C, Song Y. Neuroscientist 29 421-444 (2023)
  69. How do necrotic cells expose phosphatidylserine to attract their predators-What's unique and what's in common with apoptotic cells. Furuta Y, Zhou Z. Front Cell Dev Biol 11 1170551 (2023)
  70. Molecular logic of salt taste reception in special reference to transmembrane channel-like 4 (TMC4). Kasahara Y, Narukawa M, Takeuchi A, Tominaga M, Abe K, Asakura T. J Physiol Sci 72 31 (2022)
  71. The Role of Lipids in CRAC Channel Function. Maltan L, Andova AM, Derler I. Biomolecules 12 352 (2022)
  72. A review of the pathophysiology and the role of ion channels on bronchial asthma. Figueiredo IAD, Ferreira SRD, Fernandes JM, Silva BAD, Vasconcelos LHC, Cavalcante FA. Front Pharmacol 14 1236550 (2023)
  73. Structure and Function of Calcium-Activated Chloride Channels and Phospholipid Scramblases in the TMEM16 Family. Nguyen DM, Chen TY. Handb Exp Pharmacol 283 153-180 (2024)
  74. [Functional Expression of a Ca(2+)-activated Cl(-) Channel Modulator Involved in Ion Transport and Epithelial Cell Differentiation]. Yamazaki J. Yakugaku Zasshi 136 485-490 (2016)

Articles citing this publication (184)



Quick links