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Perforin-2 clockwise hand-over-hand pre-pore to pore transition mechanism

Author

Listed:
  • Fang Jiao

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Chinese Academy of Sciences)

  • François Dehez

    (Centre National de la Recherche Scientifique et University of Illinois at Urbana-Champaign, Unité Mixte de Recherche no 7019, Université de Lorraine)

  • Tao Ni

    (University of Oxford, Roosevelt Drive)

  • Xiulian Yu

    (University of Oxford, Roosevelt Drive
    University of Oxford)

  • Jeremy S. Dittman

    (Weill Cornell Medicine)

  • Robert Gilbert

    (University of Oxford, Roosevelt Drive
    University of Oxford)

  • Christophe Chipot

    (Centre National de la Recherche Scientifique et University of Illinois at Urbana-Champaign, Unité Mixte de Recherche no 7019, Université de Lorraine
    University of Illinois at Urbana-Champaign)

  • Simon Scheuring

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Cornell University)

Abstract

Perforin-2 (PFN2, MPEG1) is a pore-forming protein that acts as a first line of defense in the mammalian immune system, rapidly killing engulfed microbes within the phagolysosome in macrophages. PFN2 self-assembles into hexadecameric pre-pore rings that transition upon acidification into pores damaging target cell membranes. Here, using high-speed atomic force microscopy (HS-AFM) imaging and line-scanning and molecular dynamics simulation, we elucidate PFN2 pre-pore to pore transition pathways and dynamics. Upon acidification, the pre-pore rings (pre-pore-I) display frequent, 1.8 s−1, ring-opening dynamics that eventually, 0.2 s−1, initiate transition into an intermediate, short-lived, ~75 ms, pre-pore-II state, inducing a clockwise pre-pore-I to pre-pore-II propagation. Concomitantly, the first pre-pore-II subunit, undergoes a major conformational change to the pore state that propagates also clockwise at a rate ~15 s−1. Thus, the pre-pore to pore transition is a clockwise hand-over-hand mechanism that is accomplished within ~1.3 s. Our findings suggest a clockwise mechanism of membrane insertion that with variations may be general for the MACPF/CDC superfamily.

Suggested Citation

  • Fang Jiao & François Dehez & Tao Ni & Xiulian Yu & Jeremy S. Dittman & Robert Gilbert & Christophe Chipot & Simon Scheuring, 2022. "Perforin-2 clockwise hand-over-hand pre-pore to pore transition mechanism," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32757-4
    DOI: 10.1038/s41467-022-32757-4
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    References listed on IDEAS

    as
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