The complex formation between the proteins apoptosis-inducing factor (AIF) and cyclophilin A (CypA) following oxidative stress in neuronal cells has been suggested as a main target for reverting ischemia-stroke damage. Recently, a peptide encompassing AIF residues 370–394 has been developed to target the AIF-binding site on CypA, to prevent the association between the two proteins and suppress glutamate-induced cell death in neuronal cells. Using a combined approach based on NMR spectroscopy, synthesis and in vitro testing of all Ala-scan mutants of the peptide and molecular docking/molecular dynamics, we have generated a detailed model of the AIF (370–394)/CypA complex. The model suggests us that the central region of the peptide spanning residues V374–K384 mostly interacts with the protein and that for efficient complex inhibition and preservation of CypA activity, it is bent around amino acids F46–G75 of the protein. The model is consistent with experimental data also from previous works and supports the concept that the peptide does not interfere with other CypA activities unrelated to AIF activation; therefore, it may serve as an ideal template for generating future non-peptidic antagonists.
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July 2018
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The transfer of mitochondria between mesenchymal stem cells (MSCs) (red) and glioblastoma stem cells (GSCs) (green). In the zoomed inset, MSC mitochondria (labelled with asterisks) can be seen inside a GSC; for details, see pages 2305–2328.
Research Article|
July 31 2018
Binding mode of AIF(370–394) peptide to CypA: insights from NMR, label-free and molecular docking studies
Biancamaria Farina;
Biancamaria Farina
*
1Istituto di Biostrutture e Bioimmagini (IBB)-CNR and CIRPeB; Via Mezzocannone 16, Napoli 80134, Italy
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Mattia Sturlese;
Mattia Sturlese
2Molecular Modeling Section, Dipartimento di Scienze del Farmaco, Università di Padova, via F. Marzolo 5, 35131 Padova, Italy
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Fabiola Mascanzoni;
Fabiola Mascanzoni
†
1Istituto di Biostrutture e Bioimmagini (IBB)-CNR and CIRPeB; Via Mezzocannone 16, Napoli 80134, Italy
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Andrea Caporale;
Andrea Caporale
1Istituto di Biostrutture e Bioimmagini (IBB)-CNR and CIRPeB; Via Mezzocannone 16, Napoli 80134, Italy
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Alessandra Monti;
Alessandra Monti
1Istituto di Biostrutture e Bioimmagini (IBB)-CNR and CIRPeB; Via Mezzocannone 16, Napoli 80134, Italy
3Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Università degli Studi della Campania ‘Luigi Vanvitelli’, Via Vivaldi 43, 81100 Caserta, Italy
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Gianluigi Di Sorbo;
Gianluigi Di Sorbo
‡
1Istituto di Biostrutture e Bioimmagini (IBB)-CNR and CIRPeB; Via Mezzocannone 16, Napoli 80134, Italy
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Roberto Fattorusso;
Roberto Fattorusso
3Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Università degli Studi della Campania ‘Luigi Vanvitelli’, Via Vivaldi 43, 81100 Caserta, Italy
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Menotti Ruvo
;
Menotti Ruvo
1Istituto di Biostrutture e Bioimmagini (IBB)-CNR and CIRPeB; Via Mezzocannone 16, Napoli 80134, Italy
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Nunzianna Doti
1Istituto di Biostrutture e Bioimmagini (IBB)-CNR and CIRPeB; Via Mezzocannone 16, Napoli 80134, Italy
Correspondence: Nunzianna Doti (nunzianna.doti@cnr.it)
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Publisher: Portland Press Ltd
Received:
March 05 2018
Revision Received:
May 28 2018
Accepted:
June 11 2018
Accepted Manuscript online:
June 11 2018
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem J (2018) 475 (14): 2377–2393.
Article history
Received:
March 05 2018
Revision Received:
May 28 2018
Accepted:
June 11 2018
Accepted Manuscript online:
June 11 2018
Citation
Biancamaria Farina, Mattia Sturlese, Fabiola Mascanzoni, Andrea Caporale, Alessandra Monti, Gianluigi Di Sorbo, Roberto Fattorusso, Menotti Ruvo, Nunzianna Doti; Binding mode of AIF(370–394) peptide to CypA: insights from NMR, label-free and molecular docking studies. Biochem J 31 July 2018; 475 (14): 2377–2393. doi: https://doi.org/10.1042/BCJ20180177
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