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

Journal article

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.published_or_final_versio

Authors: Jiao, F; Dehez, F; Ni, T; Yu, X; Dittman, JS

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 13
• Issue: 1
• Pages: 5039-5039
• Article number: 5039
• Publication date: 2022-08-26
• DOI: 10.1038/s41467-022-32757-4
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Biophysics; Nanotechnology; Pore water pressure; Biology; Materials science; Crystallography; Chemistry; Geology; Perforin; Physics; Biochemistry; Molecular dynamics; Clockwise