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Title | Cryo-EM structures of perforin-2 in isolation and assembled on a membrane suggest a mechanism for pore formation. |
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Journal, issue, pages | EMBO J, Vol. 41, Issue 23, Page e111857, Year 2022 |
Publish date | Dec 1, 2022 |
Authors | Xiulian Yu / Tao Ni / George Munson / Peijun Zhang / Robert J C Gilbert / |
PubMed Abstract | Perforin-2 (PFN2, MPEG1) is a key pore-forming protein in mammalian innate immunity restricting intracellular bacteria proliferation. It forms a membrane-bound pre-pore complex that converts to a ...Perforin-2 (PFN2, MPEG1) is a key pore-forming protein in mammalian innate immunity restricting intracellular bacteria proliferation. It forms a membrane-bound pre-pore complex that converts to a pore-forming structure upon acidification; but its mechanism of conformational transition has been debated. Here we used cryo-electron microscopy, tomography and subtomogram averaging to determine structures of PFN2 in pre-pore and pore conformations in isolation and bound to liposomes. In isolation and upon acidification, the pre-assembled complete pre-pore rings convert to pores in both flat ring and twisted conformations. On membranes, in situ assembled PFN2 pre-pores display various degrees of completeness; whereas PFN2 pores are mainly incomplete arc structures that follow the same subunit packing arrangements as found in isolation. Both assemblies on membranes use their P2 β-hairpin for binding to the lipid membrane surface. Overall, these structural snapshots suggest a molecular mechanism for PFN2 pre-pore to pore transition on a targeted membrane, potentially using the twisted pore as an intermediate or alternative state to the flat conformation, with the capacity to cause bilayer distortion during membrane insertion. |
External links | EMBO J / PubMed:36245269 / PubMed Central |
Methods | EM (single particle) / EM (subtomogram averaging) |
Resolution | 3.0 - 18.0 Å |
Structure data | EMDB-15072, PDB-8a1d: EMDB-15076: murine perforin-2 (Mpeg1) prepore on membrane by cryoET subtomogram averaging EMDB-15086, PDB-8a1s: EMDB-15087: murine perforin-2 pore on liposome by subtomogram averaging |
Chemicals | ChemComp-NAG: ChemComp-MA4: |
Source |
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Keywords | IMMUNE SYSTEM / pore forming protein / MACPF / beta-barrel / immunity |