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The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K.

Bushell SR, Pike ACW, Falzone ME, Rorsman NJG, Ta CM, Corey RA, Newport TD, Christianson JC, Scofano LF, Shintre CA, Tessitore A, Chu A, Wang Q, Shrestha L, Mukhopadhyay SMM, Love JD, Burgess-Brown NA, Sitsapesan R, Stansfeld PJ, Huiskonen JT, Tammaro P, Accardi A, Carpenter EP
Nat Commun 10 3956 (2019)
Related entries: 6r65, 6r7x, 6r7y, 6r7z

Cited: 63 times
EuropePMC logo PMID: 31477691

Abstract

Membranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum (ER) the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase or chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity. Crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional cryo-EM structures reveal extensive conformational changes from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity.

Articles - 5oc9 mentioned but not cited (7)

  1. The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K. Bushell SR, Pike ACW, Falzone ME, Rorsman NJG, Ta CM, Corey RA, Newport TD, Christianson JC, Scofano LF, Shintre CA, Tessitore A, Chu A, Wang Q, Shrestha L, Mukhopadhyay SMM, Love JD, Burgess-Brown NA, Sitsapesan R, Stansfeld PJ, Huiskonen JT, Tammaro P, Accardi A, Carpenter EP. Nat Commun 10 3956 (2019)
  2. Structural basis of Ca2+-dependent activation and lipid transport by a TMEM16 scramblase. Falzone ME, Rheinberger J, Lee BC, Peyear T, Sasset L, Raczkowski AM, Eng ET, Di Lorenzo A, Andersen OS, Nimigean CM, Accardi A. Elife 8 e43229 (2019)
  3. Dysregulated calcium homeostasis prevents plasma membrane repair in Anoctamin 5/TMEM16E-deficient patient muscle cells. Chandra G, Defour A, Mamchoui K, Pandey K, Mishra S, Mouly V, Sreetama S, Mahad Ahmad M, Mahjneh I, Morizono H, Pattabiraman N, Menon AK, Jaiswal JK. Cell Death Discov 5 118 (2019)
  4. An outer-pore gate modulates the pharmacology of the TMEM16A channel. Dinsdale RL, Pipatpolkai T, Agostinelli E, Russell AJ, Stansfeld PJ, Tammaro P. Proc Natl Acad Sci U S A 118 e2023572118 (2021)
  5. Molecular mechanisms of ion conduction and ion selectivity in TMEM16 lipid scramblases. Kostritskii AY, Machtens JP. Nat Commun 12 2826 (2021)
  6. Design, synthesis and biological evaluations of niclosamide analogues against SARS-CoV-2. Juang YP, Chou YT, Lin RX, Ma HH, Chao TL, Jan JT, Chang SY, Liang PH. Eur J Med Chem 235 114295 (2022)
  7. The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase. Khelashvili G, Kots E, Cheng X, Levine MV, Weinstein H. Commun Biol 5 990 (2022)


Reviews citing this publication (19)

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Articles citing this publication (37)

  1. TMEM41B and VMP1 are scramblases and regulate the distribution of cholesterol and phosphatidylserine. Li YE, Wang Y, Du X, Zhang T, Mak HY, Hancock SE, McEwen H, Pandzic E, Whan RM, Aw YC, Lukmantara IE, Yuan Y, Dong X, Don A, Turner N, Qi S, Yang H. J Cell Biol 220 e202103105 (2021)
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  5. An Additional Ca2+ Binding Site Allosterically Controls TMEM16A Activation. Le SC, Yang H. Cell Rep 33 108570 (2020)
  6. Cryo-EM structures of the caspase-activated protein XKR9 involved in apoptotic lipid scrambling. Straub MS, Alvadia C, Sawicka M, Dutzler R. Elife 10 e69800 (2021)
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  8. The tertiary structure of the human Xkr8-Basigin complex that scrambles phospholipids at plasma membranes. Sakuragi T, Kanai R, Tsutsumi A, Narita H, Onishi E, Nishino K, Miyazaki T, Baba T, Kosako H, Nakagawa A, Kikkawa M, Toyoshima C, Nagata S. Nat Struct Mol Biol 28 825-834 (2021)
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  10. The NUCKS1-SKP2-p21/p27 axis controls S phase entry. Hume S, Grou CP, Lascaux P, D'Angiolella V, Legrand AJ, Ramadan K, Dianov GL. Nat Commun 12 6959 (2021)
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  13. --Atg9 interactions via its transmembrane domains are required for phagophore expansion during autophagy. Chumpen Ramirez S, Gómez-Sánchez R, Verlhac P, Hardenberg R, Margheritis E, Cosentino K, Reggiori F, Ungermann C. Autophagy 19 1459-1478 (2023)
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  16. Genome-wide CRISPR screen reveals CLPTM1L as a lipid scramblase required for efficient glycosylphosphatidylinositol biosynthesis. Wang Y, Menon AK, Maki Y, Liu YS, Iwasaki Y, Fujita M, Guerrero PA, Silva DV, Seeberger PH, Murakami Y, Kinoshita T. Proc Natl Acad Sci U S A 119 e2115083119 (2022)
  17. Whole-exome sequencing reveals ANO8 as a genetic risk factor for intrahepatic cholestasis of pregnancy. Liu X, Lai H, Zeng X, Xin S, Nie L, Liang Z, Wu M, Chen Y, Zheng J, Zou Y. BMC Pregnancy Childbirth 20 544 (2020)
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  20. Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC. Lam AKM, Rutz S, Dutzler R. Nat Commun 13 2798 (2022)
  21. A mechanical-coupling mechanism in OSCA/TMEM63 channel mechanosensitivity. Zhang M, Shan Y, Cox CD, Pei D. Nat Commun 14 3943 (2023)
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  23. A Fluorescence-based Assay for Measuring Phospholipid Scramblase Activity in Giant Unilamellar Vesicles. Mathiassen PPM, Pomorski TG. Bio Protoc 12 e4366 (2022)
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  26. Expanding the Allelic Heterogeneity of ANO10-Associated Autosomal Recessive Cerebellar Ataxia. Massey S, Guo Y, Riley LG, Van Bergen NJ, Sandaradura SA, McCusker E, Tchan M, Thauvin-Robinet C, Thomas Q, Moreau T, Davis M, Smits D, Mancini GMS, Hakonarson H, Cooper S, Christodoulou J. Neurol Genet 9 e200051 (2023)
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  31. Deciphering the Interactions of SARS-CoV-2 Proteins with Human Ion Channels Using Machine-Learning-Based Methods. Munjal NS, Sapra D, Parthasarathi KTS, Goyal A, Pandey A, Banerjee M, Sharma J. Pathogens 11 259 (2022)
  32. Extracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4. Zhang P, Maruoka M, Suzuki R, Katani H, Dou Y, Packwood DM, Kosako H, Tanaka M, Suzuki J. Nat Commun 14 5592 (2023)
  33. Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase. Feng S, Puchades C, Ko J, Wu H, Chen Y, Figueroa EE, Gu S, Han TW, Ho B, Cheng T, Li J, Shoichet B, Jan YN, Cheng Y, Jan LY. Nat Commun 14 4874 (2023)
  34. Investigation of Phosphatidylserine-Transporting Activity of Human TMEM16C Isoforms. Kim H, Kim E, Lee BC. Membranes (Basel) 12 1005 (2022)
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