Journal article

The Molecular Basis for Perforin Oligomerization and Transmembrane Pore Assembly

Katherine Baran, Michelle Dunstone, Jenny Chia, Annette Ciccone, Kylie A Browne, Christopher JP Clarke, Natalya Lukoyanova, Helen Saibil, James C Whisstock, Ilia Voskoboinik, Joseph A Trapani

IMMUNITY | CELL PRESS | Published : 2009


Perforin, a pore-forming protein secreted by cytotoxic lymphocytes, is indispensable for destroying virus-infected cells and for maintaining immune homeostasis. Perforin polymerizes into transmembrane channels that inflict osmotic stress and facilitate target cell uptake of proapoptotic granzymes. Despite this, the mechanism through which perforin monomers self-associate remains unknown. Our current study establishes the molecular basis for perforin oligomerization and pore assembly. We show that after calcium-dependent membrane binding, direct ionic attraction between the opposite faces of adjacent perforin monomers was necessary for pore formation. By using mutagenesis, we identified the o..

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Awarded by Biotechnology and Biological Sciences Research Council

Funding Acknowledgements

J.A.T. and I.V. are supported by Fellowships, a project grant, and a Program Grant from the National Health and Medical Research Council (NHMRC) of Australia. J.C.W. is an Australian Research Council Federation Fellow and is supported by a program and project grant from the NHMRC as well as a Centre of Excellence/Discovery Project from the Australian Research Council. M.D. is an NHMRC Peter Doherty Training Fellow and recipient of a Monash University Faculty of Medicine Strategic Grant Scheme Early Career Researcher award. K.B. is supported by a postdoctoral fellowship from the Cancer Council Victoria, Australia. We thank C. House for expert assistance with gel filtration experiments.