Structural and biochemical insights of CypA and AIF interaction
Abstract The Cyclophilin A (CypA)/Apoptosis Inducing Factor (AIF) complex is implicated in the DNA degradation in response to various cellular stress conditions, such as oxidative stress, cerebral hypoxia-ischemia and traumatic brain injury. The pro-apoptotic form of AIF (AIF(Δ1-121)) mainly interac...
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oai:doaj.org-article:a91821b2950a40689864374c11113d442021-12-02T16:06:36ZStructural and biochemical insights of CypA and AIF interaction10.1038/s41598-017-01337-82045-2322https://doaj.org/article/a91821b2950a40689864374c11113d442017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01337-8https://doaj.org/toc/2045-2322Abstract The Cyclophilin A (CypA)/Apoptosis Inducing Factor (AIF) complex is implicated in the DNA degradation in response to various cellular stress conditions, such as oxidative stress, cerebral hypoxia-ischemia and traumatic brain injury. The pro-apoptotic form of AIF (AIF(Δ1-121)) mainly interacts with CypA through the amino acid region 370–394. The AIF(370-394) synthetic peptide inhibits complex formation in vitro by binding to CypA and exerts neuroprotection in a model of glutamate-mediated oxidative stress. Here, the binding site of AIF(Δ1-121) and AIF(370-394) on CypA has been mapped by NMR spectroscopy and biochemical studies, and a molecular model of the complex has been proposed. We show that AIF(370-394) interacts with CypA on the same surface recognized by AIF(Δ1-121) protein and that the region is very close to the CypA catalytic pocket. Such region partially overlaps with the binding site of cyclosporin A (CsA), the strongest catalytic inhibitor of CypA. Our data point toward distinct CypA structural determinants governing the inhibitor selectivity and the differential biological effects of AIF and CsA, and provide new structural insights for designing CypA/AIF selective inhibitors with therapeutic relevance in neurodegenerative diseases.Biancamaria FarinaGianluigi Di SorboAngela ChamberyAndrea CaporaleGuido LeoniRosita RussoFabiola MascanzoniDomenico RaimondoRoberto FattorussoMenotti RuvoNunzianna DotiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017) |
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Medicine R Science Q Biancamaria Farina Gianluigi Di Sorbo Angela Chambery Andrea Caporale Guido Leoni Rosita Russo Fabiola Mascanzoni Domenico Raimondo Roberto Fattorusso Menotti Ruvo Nunzianna Doti Structural and biochemical insights of CypA and AIF interaction |
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Abstract The Cyclophilin A (CypA)/Apoptosis Inducing Factor (AIF) complex is implicated in the DNA degradation in response to various cellular stress conditions, such as oxidative stress, cerebral hypoxia-ischemia and traumatic brain injury. The pro-apoptotic form of AIF (AIF(Δ1-121)) mainly interacts with CypA through the amino acid region 370–394. The AIF(370-394) synthetic peptide inhibits complex formation in vitro by binding to CypA and exerts neuroprotection in a model of glutamate-mediated oxidative stress. Here, the binding site of AIF(Δ1-121) and AIF(370-394) on CypA has been mapped by NMR spectroscopy and biochemical studies, and a molecular model of the complex has been proposed. We show that AIF(370-394) interacts with CypA on the same surface recognized by AIF(Δ1-121) protein and that the region is very close to the CypA catalytic pocket. Such region partially overlaps with the binding site of cyclosporin A (CsA), the strongest catalytic inhibitor of CypA. Our data point toward distinct CypA structural determinants governing the inhibitor selectivity and the differential biological effects of AIF and CsA, and provide new structural insights for designing CypA/AIF selective inhibitors with therapeutic relevance in neurodegenerative diseases. |
format |
article |
author |
Biancamaria Farina Gianluigi Di Sorbo Angela Chambery Andrea Caporale Guido Leoni Rosita Russo Fabiola Mascanzoni Domenico Raimondo Roberto Fattorusso Menotti Ruvo Nunzianna Doti |
author_facet |
Biancamaria Farina Gianluigi Di Sorbo Angela Chambery Andrea Caporale Guido Leoni Rosita Russo Fabiola Mascanzoni Domenico Raimondo Roberto Fattorusso Menotti Ruvo Nunzianna Doti |
author_sort |
Biancamaria Farina |
title |
Structural and biochemical insights of CypA and AIF interaction |
title_short |
Structural and biochemical insights of CypA and AIF interaction |
title_full |
Structural and biochemical insights of CypA and AIF interaction |
title_fullStr |
Structural and biochemical insights of CypA and AIF interaction |
title_full_unstemmed |
Structural and biochemical insights of CypA and AIF interaction |
title_sort |
structural and biochemical insights of cypa and aif interaction |
publisher |
Nature Portfolio |
publishDate |
2017 |
url |
https://doaj.org/article/a91821b2950a40689864374c11113d44 |
work_keys_str_mv |
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1718384981518057472 |