Binding mode of AIF(370–394) peptide to CypA: insights from NMR, label-free and molecular docking studies
| Autor: | Mattia Sturlese, Andrea Caporale, Menotti Ruvo, Alessandra Monti, Nunzianna Doti, Fabiola Mascanzoni, Gianluigi Di Sorbo, Roberto Fattorusso, Biancamaria Farina |
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| Přispěvatelé: | Farina, Biancamaria, Sturlese, Mattia, Mascanzoni, Fabiola, Caporale, Andrea, Monti, Alessandra, Di Sorbo, Gianluigi, Fattorusso, Roberto, Ruvo, Menotti, Doti, Nunzianna |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
AIF(370–394) peptide Ala-scanning CypA NMR spectroscopy molecular modeling Magnetic Resonance Spectroscopy Molecular model Mutant Cypa Peptide Molecular Dynamics Simulation Biochemistry 03 medical and health sciences Cyclophilin A AIF(370-394) peptide 0302 clinical medicine Humans cardiovascular diseases Molecular Biology chemistry.chemical_classification biology Apoptosis Inducing Factor Cell Biology Nuclear magnetic resonance spectroscopy biology.organism_classification In vitro Cell biology Amino acid Molecular Docking Simulation 030104 developmental biology chemistry Peptides 030217 neurology & neurosurgery |
| Zdroj: | Biochemical Journal. 475:2377-2393 |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bcj20180177 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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