Journal article

The structural basis for membrane binding and pore formation by lymphocyte perforin

Ruby HP Law, Natalya Lukoyanova, Ilia Voskoboinik, Tom T Caradoc-Davies, Katherine Baran, Michelle A Dunstone, Michael E D'Angelo, Elena V Orlova, Fasseli Coulibaly, Sandra Verschoor, Kylie A Browne, Annette Ciccone, Michael J Kuiper, Phillip I Bird, Joseph A Trapani, Helen R Saibil, James C Whisstock



Natural killer cells and cytotoxic T lymphocytes accomplish the critically important function of killing virus-infected and neoplastic cells. They do this by releasing the pore-forming protein perforin and granzyme proteases from cytoplasmic granules into the cleft formed between the abutting killer and target cell membranes. Perforin, a 67-kilodalton multidomain protein, oligomerizes to form pores that deliver the pro-apoptopic granzymes into the cytosol of the target cell. The importance of perforin is highlighted by the fatal consequences of congenital perforin deficiency, with more than 50 different perforin mutations linked to familial haemophagocytic lymphohistiocytosis (type 2 FHL). H..

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Awarded by Biotechnology and Biological Sciences Research Council

Funding Acknowledgements

J.C.W. is an Australian Research Council Federation Fellow and Honorary National Health and Medical Research Council of Australia Principal Research Fellow. I.V., F.C. and M.A.D. are NHMRC Career Development Fellows. K.B. is an NHMRC C.J. Martin overseas training fellow. J.A.T. acknowledges the support of an NHMRC Senior Principal Research Fellowship during the course of the work. The authors thank the NHMRC, the ARC, the UK BBSRC and the Wellcome Trust for grant support. We thank the Australian synchrotron beamline scientists for technical support and access to the MX-2 Microfocus Beamline; we thank D. Clare and L. Wang for electron microscopy support, and D. Houldershaw, R. Westlake and K. Mahmood for computing support. We thank D. Steer and the Monash University Proteomics Unit for technical support.