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

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 propagati

SUBMITTER: Jiao F 

PROVIDER: S-EPMC9418332 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature