Defining the interaction of perforin with calcium and the phospholipid membrane

Author:

Traore Daouda A. K.123,Brennan Amelia J.45,Law Ruby H. P.12,Dogovski Con67,Perugini Matthew A.67,Lukoyanova Natalya8,Leung Eleanor W. W.3,Norton Raymond S.3,Lopez Jamie A.45,Browne Kylie A.45,Yagita Hideo9,Lloyd Gordon J.12,Ciccone Annette45,Verschoor Sandra45,Trapani Joseph A.4510,Whisstock James C.12,Voskoboinik Ilia4511

Affiliation:

1. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3052, Australia

2. The ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC 3052, Australia

3. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia

4. Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia

5. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia

6. Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3086, Australia

7. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC 3010, Australia

8. Crystallography, Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, U.K.

9. Department of Immunology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan

10. Department of Pathology, The University of Melbourne, Parkville, VIC 3010, Australia

11. Department of Genetics, The University of Melbourne, Parkville, VIC 3010, Australia

Abstract

Following its secretion from cytotoxic lymphocytes into the immune synapse, perforin binds to target cell membranes through its Ca2+-dependent C2 domain. Membrane-bound perforin then forms pores that allow passage of pro-apoptopic granzymes into the target cell. In the present study, structural and biochemical studies reveal that Ca2+ binding triggers a conformational change in the C2 domain that permits four key hydrophobic residues to interact with the plasma membrane. However, in contrast with previous suggestions, these movements and membrane binding do not trigger irreversible conformational changes in the pore-forming MACPF (membrane attack complex/perforin-like) domain, indicating that subsequent monomer–monomer interactions at the membrane surface are required for perforin pore formation.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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