Cryo-EM structures of perforin-2 in isolation and assembled on a membrane suggest a mechanism for pore formation.
EMBO J
; 41(23): e111857, 2022 12 01.
Article
em En
| MEDLINE
| ID: mdl-36245269
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 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 ß-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.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Lipossomos
/
Mamíferos
Limite:
Animals
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Reino Unido