Academic Journal
W196 and the β-Hairpin Motif Modulate the Redox Switch of Conformation and the Biomolecular Interaction Network of the Apoptosis-Inducing Factor
| العنوان: | W196 and the β-Hairpin Motif Modulate the Redox Switch of Conformation and the Biomolecular Interaction Network of the Apoptosis-Inducing Factor |
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| المؤلفون: | Silvia Romero-Tamayo, Ruben Laplaza, Adrian Velazquez-Campoy, Raquel Villanueva, Milagros Medina, Patricia Ferreira |
| المصدر: | Oxidative Medicine and Cellular Longevity, Vol 2021 (2021) |
| بيانات النشر: | Hindawi Limited |
| سنة النشر: | 2021 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Cytology, QH573-671 |
| الوصف: | The human apoptosis-inducing factor (hAIF) is a moonlight flavoprotein involved in mitochondrial respiratory complex assembly and caspase-independent programmed cell death. These functions might be modulated by its redox-linked structural transition that enables hAIF to act as a NAD(H/+) redox sensor. Upon reduction with NADH, hAIF undergoes a conformational reorganization in two specific insertions—the flexible regulatory C-loop and the 190-202 β-harpin—promoting protein dimerization and the stabilization of a long-life charge transfer complex (CTC) that modulates its monomer-dimer equilibrium and its protein interaction network in healthy mitochondria. In this regard, here, we investigated the precise function of the β-hairpin in the AIF conformation landscape related to its redox mechanism, by analyzing the role played by W196, a key residue in the interaction of this motif with the regulatory C-loop. Mutations at W196 decrease the compactness and stability of the oxidized hAIF, indicating that the β-hairpin and C-loop coupling contribute to protein stability. Kinetic studies complemented with computational simulations reveal that W196 and the β-hairpin conformation modulate the low efficiency of hAIF as NADH oxidoreductase, contributing to configure its active site in a noncompetent geometry for hydride transfer and to stabilize the CTC state by enhancing the affinity for NAD+. Finally, the β-hairpin motif contributes to define the conformation of AIF’s interaction surfaces with its physiological partners. These findings improve our understanding on the molecular basis of hAIF’s cellular activities, a crucial aspect for clarifying its associated pathological mechanisms and developing new molecular therapies. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1942-0900 1942-0994 |
| Relation: | http://dx.doi.org/10.1155/2021/6673661; https://doaj.org/toc/1942-0900; https://doaj.org/toc/1942-0994; https://doaj.org/article/24d0654827f54976a06b4761e372a335 |
| DOI: | 10.1155/2021/6673661 |
| الاتاحة: | https://doi.org/10.1155/2021/6673661 https://doaj.org/article/24d0654827f54976a06b4761e372a335 |
| رقم الانضمام: | edsbas.F35025B9 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 19420900 19420994 |
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| DOI: | 10.1155/2021/6673661 |