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Cryo-EM structure of the botulinum neurotoxin A/SV2B complex and its implications for translocation

Author

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  • Basavraj Khanppnavar

    (PSI Center for Life Sciences)

  • Oneda Leka

    (PSI Center for Life Sciences)

  • Sushant K. Pal

    (PSI Center for Life Sciences)

  • Volodymyr M. Korkhov

    (PSI Center for Life Sciences
    ETH Zurich)

  • Richard A. Kammerer

    (PSI Center for Life Sciences)

Abstract

Botulinum neurotoxin A1 (BoNT/A1) belongs to the most potent toxins and is used as a major therapeutic agent. Neurotoxin conformation is crucial for its translocation to the neuronal cytosol, a key process for intoxication that is only poorly understood. To gain molecular insights into the steps preceding toxin translocation, we determine cryo-EM structures of BoNT/A1 alone and in complex with its receptor synaptic vesicle glycoprotein 2B (SV2B). In solution, BoNT/A1 adopts a unique, semi-closed conformation. The toxin changes its structure into an open state upon receptor binding with the translocation domain (HN) and the catalytic domain (LC) remote from the membrane, suggesting translocation incompatibility. Under acidic pH conditions, where translocation is initiated, receptor-bound BoNT/A1 switches back into a semi-closed conformation. This conformation brings the LC and HN close to the membrane, suggesting that a translocation-competent state of the toxin is required for successful LC transport into the neuronal cytosol.

Suggested Citation

  • Basavraj Khanppnavar & Oneda Leka & Sushant K. Pal & Volodymyr M. Korkhov & Richard A. Kammerer, 2025. "Cryo-EM structure of the botulinum neurotoxin A/SV2B complex and its implications for translocation," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56304-z
    DOI: 10.1038/s41467-025-56304-z
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    1. Oneda Leka & Yufan Wu & Giulia Zanetti & Sven Furler & Thomas Reinberg & Joana Marinho & Jonas V. Schaefer & Andreas Plückthun & Xiaodan Li & Marco Pirazzini & Richard A. Kammerer, 2023. "A DARPin promotes faster onset of botulinum neurotoxin A1 action," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    3. Basavraj Khanppnavar & Julian Maier & Freja Herborg & Ralph Gradisch & Erika Lazzarin & Dino Luethi & Jae-Won Yang & Chao Qi & Marion Holy & Kathrin Jäntsch & Oliver Kudlacek & Klaus Schicker & Thomas, 2022. "Structural basis of organic cation transporter-3 inhibition," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Kwok-ho Lam & Zhuojun Guo & Nadja Krez & Tsutomu Matsui & Kay Perry & Jasmin Weisemann & Andreas Rummel & Mark E. Bowen & Rongsheng Jin, 2018. "A viral-fusion-peptide-like molecular switch drives membrane insertion of botulinum neurotoxin A1," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    5. Roger M. Benoit & Daniel Frey & Manuel Hilbert & Josta T. Kevenaar & Mara M. Wieser & Christian U. Stirnimann & David McMillan & Tom Ceska & Florence Lebon & Rolf Jaussi & Michel O. Steinmetz & Gebhar, 2014. "Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A," Nature, Nature, vol. 505(7481), pages 108-111, January.
    6. Yi C. Zeng & Meghna Sobti & Ada Quinn & Nicola J. Smith & Simon H. J. Brown & Jamie I. Vandenberg & Renae M. Ryan & Megan L. O’Mara & Alastair G. Stewart, 2023. "Structural basis of promiscuous substrate transport by Organic Cation Transporter 1," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Atsushi Yamagata & Kaori Ito & Takehiro Suzuki & Naoshi Dohmae & Tohru Terada & Mikako Shirouzu, 2024. "Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    8. Sicai Zhang & Geoffrey Masuyer & Jie Zhang & Yi Shen & Daniel Lundin & Linda Henriksson & Shin-Ichiro Miyashita & Markel Martínez-Carranza & Min Dong & Pål Stenmark, 2017. "Identification and characterization of a novel botulinum neurotoxin," Nature Communications, Nature, vol. 8(1), pages 1-10, August.
    9. Zheng Liu & Pyung-Gang Lee & Nadja Krez & Kwok-ho Lam & Hao Liu & Adina Przykopanski & Peng Chen & Guorui Yao & Sicai Zhang & Jacqueline M. Tremblay & Kay Perry & Charles B. Shoemaker & Andreas Rummel, 2023. "Structural basis for botulinum neurotoxin E recognition of synaptic vesicle protein 2," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    10. Ellis Chika Onwordi & Els F. Halff & Thomas Whitehurst & Ayla Mansur & Marie-Caroline Cotel & Lisa Wells & Hannah Creeney & David Bonsall & Maria Rogdaki & Ekaterina Shatalina & Tiago Reis Marques & E, 2020. "Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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