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A DARPin promotes faster onset of botulinum neurotoxin A1 action

Author

Listed:
  • Oneda Leka

    (Division of Biology, Paul Scherrer Institut)

  • Yufan Wu

    (Division of Biology, Paul Scherrer Institut)

  • Giulia Zanetti

    (University of Padova)

  • Sven Furler

    (University of Zurich)

  • Thomas Reinberg

    (University of Zurich)

  • Joana Marinho

    (University of Zurich)

  • Jonas V. Schaefer

    (University of Zurich)

  • Andreas Plückthun

    (University of Zurich)

  • Xiaodan Li

    (Division of Biology, Paul Scherrer Institut)

  • Marco Pirazzini

    (University of Padova)

  • Richard A. Kammerer

    (Division of Biology, Paul Scherrer Institut)

Abstract

In this study, we characterize Designed Ankyrin Repeat Proteins (DARPins) as investigative tools to probe botulinum neurotoxin A1 (BoNT/A1) structure and function. We identify DARPin-F5 that completely blocks SNAP25 substrate cleavage by BoNT/A1 in vitro. X-ray crystallography reveals that DARPin-F5 inhibits BoNT/A1 activity by interacting with a substrate-binding region between the α- and β-exosite. This DARPin does not block substrate cleavage of BoNT/A3, indicating that DARPin-F5 is a subtype-specific inhibitor. BoNT/A1 Glu-171 plays a critical role in the interaction with DARPin-F5 and its mutation to Asp, the residue found in BoNT/A3, results in a loss of inhibition of substrate cleavage. In contrast to the in vitro results, DARPin-F5 promotes faster substrate cleavage of BoNT/A1 in primary neurons and muscle tissue by increasing toxin translocation. Our findings could have important implications for the application of BoNT/A1 in therapeutic areas requiring faster onset of toxin action combined with long persistence.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44102-4
    DOI: 10.1038/s41467-023-44102-4
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    References listed on IDEAS

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    1. 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.
    2. Mark A. Breidenbach & Axel T. Brunger, 2004. "Substrate recognition strategy for botulinum neurotoxin serotype A," Nature, Nature, vol. 432(7019), pages 925-929, December.
    3. 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.
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