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PMID:20889983

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Citation

Praper, T, Sonnen, A, Viero, G, Kladnik, A, Froelich, CJ, Anderluh, G, Dalla Serra, M and Gilbert, RJ (2011) Human perforin employs different avenues to damage membranes. J. Biol. Chem. 286:2946-55

Abstract

Perforin (PFN) is a pore-forming protein produced by cytotoxic lymphocytes that aids in the clearance of tumor or virus-infected cells by a mechanism that involves the formation of transmembrane pores. The properties of PFN pores and the mechanism of their assembly remain unclear. Here, we studied pore characteristics by functional and structural methods to show that perforin forms pores more heterogeneous than anticipated. Planar lipid bilayer experiments indicate that perforin pores exhibit a broad range of conductances, from 0.15 to 21 nanosiemens. In comparison with large pores that possessed low noise and remained stably open, small pores exhibited high noise and were very unstable. Furthermore, the opening step and the pore size were dependent on the lipid composition of the membrane. The heterogeneity in pore sizes was confirmed with cryo-electron microscopy and showed a range of sizes matching that observed in the conductance measurements. Furthermore, two different membrane-bound PFN conformations were observed, interpreted as pre-pore and pore states of the protein. The results collectively indicate that PFN forms heterogeneous pores through a multistep mechanism and provide a new paradigm for understanding the range of different effects of PFN and related membrane attack complex/perforin domain proteins observed in vivo and in vitro.

Links

PubMed PMC3024789 Online version:10.1074/jbc.M110.169417

Keywords

Cell Membrane/chemistry; Cell Membrane/metabolism; Cryoelectron Microscopy; Humans; Lipid Bilayers/chemistry; Lipid Bilayers/metabolism; Perforin/chemistry; Perforin/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PERF

located_in

GO:0016021: integral component of membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PERF

involved_in

GO:0051260: protein homooligomerization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PERF

enables

GO:0022829: wide pore channel activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PERF

part_of

GO:0016021: integral component of membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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