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]

Contents

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. [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

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]

Related Research Articles

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References

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  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. 1 2 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.
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  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. 1 2 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.
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  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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