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

Fang Jiao (), François Dehez, Tao Ni, Xiulian Yu, Jeremy S. Dittman, Robert Gilbert, Christophe Chipot and Simon Scheuring ()
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Fang Jiao: Weill Cornell Medicine
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
Jeremy S. Dittman: Weill Cornell Medicine
Robert Gilbert: University of Oxford, Roosevelt Drive
Christophe Chipot: Centre National de la Recherche Scientifique et University of Illinois at Urbana-Champaign, Unité Mixte de Recherche no 7019, Université de Lorraine
Simon Scheuring: Weill Cornell Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32757-4

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