Real-time visualization of perforin nanopore assembly

Leung, C. and Hodel, A.W. and Brennan, A. and Lukoyanova, N. and Tran, S. and House, C.M. and Kondos, S.C. and Whisstock, J.C. and Dunstone, M.A. and Trapani, J.A. and Voskoboinik, I. and Saibil, Helen R. and Hoogenboom, B.W. (2017) Real-time visualization of perforin nanopore assembly. Nature Nanotechnology , ISSN 1748-3387.

Abstract

Perforin is a key protein of the vertebrate imm une system. Secreted by cytotoxic lymphocytes as soluble monomers, perforin can self-assemble into oligomeric pores of 10-20 nm inner diameter in the membranes of virus-infected and cancerous cells. These large pores facilitate the entry of pro-apoptopic granzymes, thereby rapidly killing the target cell. To elucidate the pathways of perforin pore assembly, we have carried out real-time atomic force microscopy and electron microscopy studies. Our experiments reveal that the pore assembly proceeds via a membrane- bound prepore intermediate state, typically cons isting of up to ~8 loosely but irreversibly assembled monomeric subunits. These short oligomers convert to more closely packed membrane nanopore assemblies, which can subseque ntly recruit additional prepore oligomers to grow the pore size.

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