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.
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Research Article|
November 22 2013
Defining the interaction of perforin with calcium and the phospholipid membrane
Daouda A. K. Traore;
Daouda A. K. Traore
1
*Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3052, Australia
†The ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC 3052, Australia
‡Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
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Amelia J. Brennan;
Amelia J. Brennan
1
§Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia
∥Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
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Ruby H. P. Law;
Ruby H. P. Law
*Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3052, Australia
†The ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC 3052, Australia
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Con Dogovski;
Con Dogovski
¶Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3086, Australia
**Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC 3010, Australia
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Matthew A. Perugini;
Matthew A. Perugini
¶Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3086, Australia
**Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC 3010, Australia
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Natalya Lukoyanova;
Natalya Lukoyanova
††Crystallography, Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, U.K.
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Eleanor W. W. Leung;
Eleanor W. W. Leung
‡Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
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Raymond S. Norton;
Raymond S. Norton
‡Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
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Jamie A. Lopez;
Jamie A. Lopez
§Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia
∥Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
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Kylie A. Browne;
Kylie A. Browne
§Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia
∥Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
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Hideo Yagita;
Hideo Yagita
‡‡Department of Immunology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan
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Gordon J. Lloyd;
Gordon J. Lloyd
*Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3052, Australia
†The ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC 3052, Australia
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Annette Ciccone;
Annette Ciccone
§Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia
∥Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
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Sandra Verschoor;
Sandra Verschoor
§Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia
∥Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
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Joseph A. Trapani;
Joseph A. Trapani
§Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia
∥Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
§§Department of Pathology, The University of Melbourne, Parkville, VIC 3010, Australia
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James C. Whisstock;
James C. Whisstock
2
*Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3052, Australia
†The ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC 3052, Australia
2Correspondence may be addressed to either of these joint senior authors (email james.whisstock@monash.edu or ilia.voskoboinik@petermac.org).
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Ilia Voskoboinik
Ilia Voskoboinik
2
§Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia
∥Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
∥∥Department of Genetics, The University of Melbourne, Parkville, VIC 3010, Australia
2Correspondence may be addressed to either of these joint senior authors (email james.whisstock@monash.edu or ilia.voskoboinik@petermac.org).
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Publisher: Portland Press Ltd
Received:
July 30 2013
Revision Received:
August 23 2013
Accepted:
September 27 2013
Accepted Manuscript online:
September 27 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 456 (3): 323–335.
Article history
Received:
July 30 2013
Revision Received:
August 23 2013
Accepted:
September 27 2013
Accepted Manuscript online:
September 27 2013
Citation
Daouda A. K. Traore, Amelia J. Brennan, Ruby H. P. Law, Con Dogovski, Matthew A. Perugini, Natalya Lukoyanova, Eleanor W. W. Leung, Raymond S. Norton, Jamie A. Lopez, Kylie A. Browne, Hideo Yagita, Gordon J. Lloyd, Annette Ciccone, Sandra Verschoor, Joseph A. Trapani, James C. Whisstock, Ilia Voskoboinik; Defining the interaction of perforin with calcium and the phospholipid membrane. Biochem J 15 December 2013; 456 (3): 323–335. doi: https://doi.org/10.1042/BJ20130999
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