Atlastin Explained

Atlastins (ATLs) are a class of endoplasmic reticulum (ER) GTPases. Invertebrates have a single ATL, while vertebrates possess three ATL proteins (ATL1-3) that are differentially expressed.[1] ATL1 is the predominant paralog of the central nervous system, whereas ATL2 and ATL3 are mainly expressed in tissues outside of the CNS. Loss of all ATLs in mammalian cells dramatically impacts ER structure, including a reduction in tubule three-way junctions.[2]

Function and Regulation

ATLs maintain the ER tubular network via homotypic fusion. ATLs have a conserved domain structure consisting of a globular G domain, a three-helix bundle,[3] two transmembrane domains, and an amphipathic helix.[4] The ATL fusion cycle consists of two ATL monomers in opposing membranes binding GTP, which induces trans G domain dimerization and a crossing over of the three-helix bundle.[5] [6] Crossover and subsequent insertion of the amphipathic helix into the lipid bilayer triggers lipids to mix for fusion.[7] Lastly, GTP is hydrolyzed driving the dimer to disassembly and resetting the fusion machinery.[8] [9]

While most of the human ATL protein structure is conserved between paralogs,[10] the proteins have non-conserved N- and C-termini with the C-termini of ATL1 and ATL2 being autoinhibitory.[11] ATL1 has been shown to interact with a range of proteins including spastin and REEP1,[12] with spastin enhancing ATL1 fusion activity in vitro.[13] ATL1 and ATL2 have also been observed as interacting with ER protein TMCC3,[14] and ATL3 with nonstructural viral proteins,[15] however it is not currently known how these interactions modulate protein function.

ATLs and Disease

Mutations in ATLs are linked to human disease. Mutations in ATL3 are associated with hereditary sensory neuropathy (HSN),[16] and mutations in ATL1 are linked to HSN[17] and hereditary spastic paraplegia (HSP). Research has identified a number of mutations that correspond to the disease phenotype, including the ATL3 Y192C[18] disease mutation that is equivalent to the Y196C mutation in ATL1. Work to identify disease mutants remains ongoing, with a novel nonsense ATL3 mutation being identified in early 2023.[19] ATL3 HSN mutations affect the protein’s fusion cycle by causing aberrant tethering.[20] Similarly, an ATL1 HSP mutation was shown to increase tethering but not impact GTPase activity.[21]

Notes and References

  1. Rismanchi N, Soderblom C, Stadler J, Zhu PP, Blackstone C . Atlastin GTPases are required for Golgi apparatus and ER morphogenesis . Human Molecular Genetics . 17 . 11 . 1591–1604 . June 2008 . 18270207 . 2902292 . 10.1093/hmg/ddn046 .
  2. Zhao G, Zhu PP, Renvoisé B, Maldonado-Báez L, Park SH, Blackstone C . Mammalian knock out cells reveal prominent roles for atlastin GTPases in ER network morphology . Experimental Cell Research . 349 . 1 . 32–44 . November 2016 . 27669642 . 10.1016/j.yexcr.2016.09.015 .
  3. Bian . Xin . Klemm . Robin W. . Liu . Tina Y. . Zhang . Miao . Sun . Sha . Sui . Xuewu . Liu . Xinqi . Rapoport . Tom A. . Hu . Junjie . 2011-03-08 . Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes . Proceedings of the National Academy of Sciences . en . 108 . 10 . 3976–3981 . 10.1073/pnas.1101643108 . free . 0027-8424 . 3054032 . 21368113. 2011PNAS..108.3976B .
  4. Liu . Tina Y. . Bian . Xin . Sun . Sha . Hu . Xiaoyu . Klemm . Robin W. . Prinz . William A. . Rapoport . Tom A. . Hu . Junjie . 2012-08-07 . Lipid interaction of the C terminus and association of the transmembrane segments facilitate atlastin-mediated homotypic endoplasmic reticulum fusion . Proceedings of the National Academy of Sciences . en . 109 . 32 . E2146-54 . 10.1073/pnas.1208385109 . free . 0027-8424 . 3420179 . 22802620.
  5. Byrnes . Laura J . Singh . Avtar . Szeto . Kylan . Benvin . Nicole M . O’Donnell . John P . Zipfel . Warren R . Sondermann . Holger . 2013-01-18 . Structural basis for conformational switching and GTP loading of the large G protein atlastin . The EMBO Journal . 32 . 3 . 369–384 . 10.1038/emboj.2012.353 . 0261-4189 . 3567502 . 23334294.
  6. Byrnes . Laura J. . Sondermann . Holger . 2011-02-08 . Structural basis for the nucleotide-dependent dimerization of the large G protein atlastin-1/SPG3A . Proceedings of the National Academy of Sciences . en . 108 . 6 . 2216–2221 . 10.1073/pnas.1012792108 . free . 0027-8424 . 3038741 . 21220294.
  7. Faust . Joseph E. . Desai . Tanvi . Verma . Avani . Ulengin . Idil . Sun . Tzu-Lin . Moss . Tyler J. . Betancourt-Solis . Miguel A. . Huang . Huey W. . Lee . Tina . McNew . James A. . February 2015 . The Atlastin C-terminal Tail Is an Amphipathic Helix That Perturbs the Bilayer Structure during Endoplasmic Reticulum Homotypic Fusion . Journal of Biological Chemistry . en . 290 . 8 . 4772–4783 . 10.1074/jbc.M114.601823 . free . 4335215 . 25555915.
  8. Crosby . Daniel . Lee . Tina H. . 2022-12-01 . Munson . Mary . Membrane fusion by Drosophila atlastin does not require GTP hydrolysis . Molecular Biology of the Cell . en . 33 . 14 . br23 . 10.1091/mbc.E22-05-0164 . 1059-1524 . 9727788 . 36129776.
  9. James Winsor . Ursula Machi . Qixiu Han . David D. Hackney . Tina H. Lee . December 2018 . GTP hydrolysis promotes disassembly of the atlastin crossover dimer during ER fusion . Journal of Cell Biology . 217 . 12 . 4184–4198 . 10.1083/jcb.201805039 . 6279388 . 30249723.
  10. Hu . Xiaoyu . Wu . Fuyun . Sun . Sha . Yu . Wenying . Hu . Junjie . April 2015 . Human atlastin GTPases mediate differentiated fusion of endoplasmic reticulum membranes . Protein & Cell . en . 6 . 4 . 307–311 . 1674-800X . 10.1007/s13238-015-0139-3 . 4383757 . 25773277.
  11. Crosby . Daniel . Mikolaj . Melissa R. . Nyenhuis . Sarah B. . Bryce . Samantha . Hinshaw . Jenny E. . Lee . Tina H. . 2021-11-24 . Reconstitution of human atlastin fusion activity reveals autoinhibition by the C terminus . Journal of Cell Biology . 221 . 2 . 10.1083/jcb.202107070 . 0021-9525 . 8624677 . 34817557.
  12. Park . Seong H. . Zhu . Peng-Peng . Parker . Rell L. . Blackstone . Craig . 2010-04-01 . Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network . Journal of Clinical Investigation . en . 120 . 4 . 1097–1110 . 10.1172/JCI40979 . 0021-9738 . 2846052 . 20200447.
  13. Jang . Eunhong . Moon . Yeojin . Yoon . So Young . Diaz . Joyce Anne R. . Lee . Miriam . Ko . Naho . Park . Jongseo . Eom . Soo Hyun . Lee . Changwook . Jun . Youngsoo . 2023-02-09 . Human atlastins are sufficient to drive the fusion of liposomes with a physiological lipid composition . Journal of Cell Biology . 222 . 4 . 10.1083/jcb.202109090 . 0021-9525 . 9949273 . 36757370.
  14. Sindhu Wisesa . Yasunori Yamamoto . Toshiaki Sakisaka . TMCC3 localizes at the three-way junctions for the proper tubular network of the endoplasmic reticulum. Biochem . Biochemical Journal . November 2019 . 476 . 21 . 3241–3260 . 10.1042/BCJ20190359. 31696206 . 20.500.14094/D1007853 . free .
  15. Monel . Blandine . Rajah . Maaran Michael . Hafirassou . Mohamed Lamine . Sid Ahmed . Samy . Burlaud-Gaillard . Julien . Zhu . Peng-Peng . Nevers . Quentin . Buchrieser . Julian . Porrot . Françoise . Meunier . Cécile . Amraoui . Sonia . Chazal . Maxime . Salles . Audrey . Jouvenet . Nolwenn . Roingeard . Philippe . December 2019 . Heise . Mark T. . Atlastin Endoplasmic Reticulum-Shaping Proteins Facilitate Zika Virus Replication . Journal of Virology . en . 93 . 23 . e01047–19 . 10.1128/JVI.01047-19 . 0022-538X . 6854498 . 31534046.
  16. Kornak . Uwe . Mademan . Inès . Schinke . Marte . Voigt . Martin . Krawitz . Peter . Hecht . Jochen . Barvencik . Florian . Schinke . Thorsten . Gießelmann . Sebastian . Beil . F. Timo . Pou-Serradell . Adolf . Vílchez . Juan J. . Beetz . Christian . Deconinck . Tine . Timmerman . Vincent . March 2014 . Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3 . Brain . en . 137 . 3 . 683–692 . 10.1093/brain/awt357 . 24459106 . 1460-2156. 11858/00-001M-0000-0025-78D5-2 . free .
  17. Leonardis . L. . Auer-Grumbach . M. . Papić . L. . Zidar . J. . July 2012 . The N355K atlastin 1 mutation is associated with hereditary sensory neuropathy and pyramidal tract features . European Journal of Neurology . 19 . 7 . 992–998 . 10.1111/j.1468-1331.2012.03665.x . 1468-1331 . 22340599.
  18. Fischer . Dirk . Schabhüttl . Maria . Wieland . Thomas . Windhager . Reinhard . Strom . Tim M. . Auer-Grumbach . Michaela . July 2014 . A novel missense mutation confirms ATL3 as a gene for hereditary sensory neuropathy type 1 . Brain: A Journal of Neurology . 137 . Pt 7 . e286 . 10.1093/brain/awu091 . 1460-2156 . 24736309. free .
  19. Mohammadi . Sanaz . Jafari Khamirani . Hossein . Baneshi . Maryam . Kamal . Neda . Manoocheri . Jamal . Saffar . Mahsa . Dianatpour . Mehdi . Tabei . Seyed Mohammad Bagher . Dastgheib . Seyed Alireza . 2023-03-01 . A novel nonsense variant in the ATL3 gene is associated with disturbed pain sensitivity, numbness of distal limbs and muscle weakness . Annals of Human Genetics . 87 . 4 . 147–157 . 10.1111/ahg.12501 . 1469-1809 . 36856139.
  20. Krols . Michiel . Detry . Sammy . Asselbergh . Bob . Almeida-Souza . Leonardo . Kremer . Anna . Lippens . Saskia . De Rycke . Riet . De Winter . Vicky . Müller . Franz-Josef . Kurth . Ingo . McMahon . Harvey T. . Savvides . Savvas N. . Timmerman . Vincent . Janssens . Sophie . 2018-05-15 . Sensory-Neuropathy-Causing Mutations in ATL3 Cause Aberrant ER Membrane Tethering . Cell Reports . 23 . 7 . 2026–2038 . 10.1016/j.celrep.2018.04.071 . 2211-1247 . 29768202. free . 1854/LU-8565007 . free .
  21. Kelly . Carolyn M. . Zeiger . Peter J. . Narayanan . Vinodh . Ramsey . Keri . Sondermann . Holger . January 2022 . A novel insertion mutation in atlastin 1 is associated with spastic quadriplegia, increased membrane tethering, and aberrant conformational switching . The Journal of Biological Chemistry . 298 . 1 . 101438 . 10.1016/j.jbc.2021.101438 . free . 1083-351X . 8688574 . 34808209.

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