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Atlastin

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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.[1] Loss of all ATLs in mammalian cells dramatically impacts ER structure, including a reduction in tubule three-way junctions.[2]

Function and Regulation

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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.[3][5][6] Crossover and subsequent insertion of the amphipathic helix into the lipid bilayer triggers lipids to mix for fusion.[4][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[1] 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

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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).[12] 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.[6] 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]

References

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  1. ^ a b c Rismanchi N, Soderblom C, Stadler J, Zhu PP, Blackstone C (June 2008). "Atlastin GTPases are required for Golgi apparatus and ER morphogenesis". Human Molecular Genetics. 17 (11): 1591–1604. doi:10.1093/hmg/ddn046. PMC 2902292. PMID 18270207.
  2. ^ Zhao G, Zhu PP, Renvoisé B, Maldonado-Báez L, Park SH, Blackstone C (November 2016). "Mammalian knock out cells reveal prominent roles for atlastin GTPases in ER network morphology". Experimental Cell Research. 349 (1): 32–44. doi:10.1016/j.yexcr.2016.09.015. PMID 27669642.
  3. ^ a b 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. 108 (10): 3976–3981. Bibcode:2011PNAS..108.3976B. doi:10.1073/pnas.1101643108. ISSN 0027-8424. PMC 3054032. PMID 21368113.
  4. ^ a b 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. 109 (32): E2146-54. doi:10.1073/pnas.1208385109. ISSN 0027-8424. PMC 3420179. PMID 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. doi:10.1038/emboj.2012.353. ISSN 0261-4189. PMC 3567502. PMID 23334294.
  6. ^ a b 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. 108 (6): 2216–2221. doi:10.1073/pnas.1012792108. ISSN 0027-8424. PMC 3038741. PMID 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. 290 (8): 4772–4783. doi:10.1074/jbc.M114.601823. PMC 4335215. PMID 25555915.
  8. ^ Crosby, Daniel; Lee, Tina H. (2022-12-01). Munson, Mary (ed.). "Membrane fusion by Drosophila atlastin does not require GTP hydrolysis". Molecular Biology of the Cell. 33 (14): br23. doi:10.1091/mbc.E22-05-0164. ISSN 1059-1524. PMC 9727788. PMID 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. doi:10.1083/jcb.201805039. PMC 6279388. PMID 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. 6 (4): 307–311. doi:10.1007/s13238-015-0139-3. ISSN 1674-800X. PMC 4383757. PMID 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). doi:10.1083/jcb.202107070. ISSN 0021-9525. PMC 8624677. PMID 34817557.
  12. ^ a b 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. 120 (4): 1097–1110. doi:10.1172/JCI40979. ISSN 0021-9738. PMC 2846052. PMID 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). doi:10.1083/jcb.202109090. ISSN 0021-9525. PMC 9949273. PMID 36757370.
  14. ^ Sindhu Wisesa; Yasunori Yamamoto; Toshiaki Sakisaka (November 2019). "TMCC3 localizes at the three-way junctions for the proper tubular network of the endoplasmic reticulum. Biochem". Biochemical Journal. 476 (21): 3241–3260. doi:10.1042/BCJ20190359. hdl:20.500.14094/D1007853. PMID 31696206.
  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. (ed.). "Atlastin Endoplasmic Reticulum-Shaping Proteins Facilitate Zika Virus Replication". Journal of Virology. 93 (23): e01047–19. doi:10.1128/JVI.01047-19. ISSN 0022-538X. PMC 6854498. PMID 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. 137 (3): 683–692. doi:10.1093/brain/awt357. hdl:11858/00-001M-0000-0025-78D5-2. ISSN 1460-2156. PMID 24459106.
  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. doi:10.1111/j.1468-1331.2012.03665.x. ISSN 1468-1331. PMID 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. doi:10.1093/brain/awu091. ISSN 1460-2156. PMID 24736309.
  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. doi:10.1111/ahg.12501. ISSN 1469-1809. PMID 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. doi:10.1016/j.celrep.2018.04.071. hdl:1854/LU-8565007. ISSN 2211-1247. PMID 29768202.
  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. doi:10.1016/j.jbc.2021.101438. ISSN 1083-351X. PMC 8688574. PMID 34808209.
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