Defining the interaction of perforin with calcium and the phospholipid membrane

Daouda AK Traore; Amelia J Brennan; Ruby HP Law; Con Dogovski; Matthew A Perugini; Natalya Lukoyanova; Eleanor WW 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

Journal article

Defining the interaction of perforin with calcium and the phospholipid membrane

Daouda AK Traore, Amelia J Brennan, Ruby HP Law, Con Dogovski, Matthew A Perugini, Natalya Lukoyanova, Eleanor WW 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

BIOCHEMICAL JOURNAL | PORTLAND PRESS LTD | Published : 2013

DOI: 10.1042/BJ20130999

Abstract

Following its secretion from cytotoxic lymphocytes into the immune synapse, perforin binds to target cell membranes through its Ca(2+)-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 Ca(2+) 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..

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University of Melbourne Researchers

Matt Perugini Author Biochemistry and Pharmacology

Ilia Voskoboinik Author The Sir Peter Maccallum Department of Oncology

Joseph Trapani Author The Sir Peter Maccallum Department of Oncology

Amelia Jayne Brennan Author The Sir Peter Maccallum Department of Oncology

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Grants

Awarded by NHMRC Australia

Awarded by Wellcome Trust

Funding Acknowledgements

D.A.K.T. is an Australian Research Council (ARC) Super Science Fellow. A.J.B. and J.A.L. are National Health and Medical Research Council (NHMRC) of Australia Training Fellows. MAP. is an ARC Future Fellow. I.V. is an NHMRC Career Development Fellow. J.C.W. is an ARC Federation Fellow and an honorary NHMRC Principal Research Fellow. R.S.N. is an NHMRC Principal Research Fellow. The work was financially supported by Project Grants from the NHMRC Australia [APP606557 and APP1029295]. We acknowledge the Wellcome Trust [grant number 079605/2/06/2 for their support for the Electron Microscopy facilities at Birkbeck College.