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pH- and concentration-dependent supramolecular assembly of a fungal defensin plectasin variant into helical non-amyloid fibrils

Author

Listed:
  • Christin Pohl

    (Novozymes A/S
    Technical University of Denmark, Department of Chemistry
    Lund University)

  • Gregory Effantin

    (Univ. Grenoble Alpes, CNRS, CEA, Institute for Structural Biology)

  • Eaazhisai Kandiah

    (European Synchrotron Radiation Facility)

  • Sebastian Meier

    (Technical University of Denmark, Department of Chemistry)

  • Guanghong Zeng

    (DFM A/S (Danish National Metrology Institute)
    Novo Nordisk)

  • Werner Streicher

    (Novozymes A/S
    NanoTemper Technologies GmbH)

  • Dorotea Raventos Segura

    (Novozymes A/S)

  • Per H. Mygind

    (Novozymes A/S
    Ascendis Pharma A/S)

  • Dorthe Sandvang

    (Novozymes A/S
    Chr. Hansen A/S)

  • Line Anker Nielsen

    (Novozymes A/S)

  • Günther H. J. Peters

    (Technical University of Denmark, Department of Chemistry)

  • Guy Schoehn

    (Univ. Grenoble Alpes, CNRS, CEA, Institute for Structural Biology)

  • Christoph Mueller-Dieckmann

    (European Synchrotron Radiation Facility)

  • Allan Noergaard

    (Novozymes A/S)

  • Pernille Harris

    (Technical University of Denmark, Department of Chemistry
    University of Copenhagen)

Abstract

Self-assembly and fibril formation play important roles in protein behaviour. Amyloid fibril formation is well-studied due to its role in neurodegenerative diseases and characterized by refolding of the protein into predominantly β-sheet form. However, much less is known about the assembly of proteins into other types of supramolecular structures. Using cryo-electron microscopy at a resolution of 1.97 Å, we show that a triple-mutant of the anti-microbial peptide plectasin, PPI42, assembles into helical non-amyloid fibrils. The in vitro anti-microbial activity was determined and shown to be enhanced compared to the wildtype. Plectasin contains a cysteine-stabilised α-helix-β-sheet structure, which remains intact upon fibril formation. Two protofilaments form a right-handed protein fibril. The fibril formation is reversible and follows sigmoidal kinetics with a pH- and concentration dependent equilibrium between soluble monomer and protein fibril. This high-resolution structure reveals that α/β proteins can natively assemble into fibrils.

Suggested Citation

  • Christin Pohl & Gregory Effantin & Eaazhisai Kandiah & Sebastian Meier & Guanghong Zeng & Werner Streicher & Dorotea Raventos Segura & Per H. Mygind & Dorthe Sandvang & Line Anker Nielsen & Günther H., 2022. "pH- and concentration-dependent supramolecular assembly of a fungal defensin plectasin variant into helical non-amyloid fibrils," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30462-w
    DOI: 10.1038/s41467-022-30462-w
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    References listed on IDEAS

    as
    1. Per H. Mygind & Rikke L. Fischer & Kirk M. Schnorr & Mogens T. Hansen & Carsten P. Sönksen & Svend Ludvigsen & Dorotea Raventós & Steen Buskov & Bjarke Christensen & Leonardo De Maria & Olivier Tabour, 2005. "Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus," Nature, Nature, vol. 437(7061), pages 975-980, October.
    2. Hector Garcia-Seisdedos & Charly Empereur-Mot & Nadav Elad & Emmanuel D. Levy, 2017. "Proteins evolve on the edge of supramolecular self-assembly," Nature, Nature, vol. 548(7666), pages 244-247, August.
    3. Md Anisur Rahman & Marpe Bam & Edgar Luat & Moumita Sharmin Jui & Mitra S. Ganewatta & Tinom Shokfai & Mitzi Nagarkatti & Alan W. Decho & Chuanbing Tang, 2018. "Macromolecular-clustered facial amphiphilic antimicrobials," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    4. Yizhaq Engelberg & Meytal Landau, 2020. "The Human LL-37(17-29) antimicrobial peptide reveals a functional supramolecular structure," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
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