期刊
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
卷 20, 期 -, 页码 3695-3707出版社
ELSEVIER
DOI: 10.1016/j.csbj.2022.07.009
关键词
Cytochrome c; Encounter complex; Protein phosphatase 2A; Molecular dynamics; Nuclear magnetic resonance; SET/TAF-I beta
资金
- Ministry of Science and Innovation [PID2021-126663NB-I00, PGC2018-096049-B-I00, BFU201571017]
- European Regional Development Fund (FEDER)
- Andalusian Government [BIO-198, US-1254317, US-1257019, P18-FR3487, P18-HO-4091]
- University of Seville (VI PPIT)
- Ramon Areces Foundation
- Ministry of Education and Professional Training [FPU18/06577, FPU013/04373]
- German Federal Ministry of Education and Research [FKZ 16QK10A]
- NIH [P41-GM103311]
- Biointeractomicts Platform (cicCartuja, Seville)
- IR INFRANALYTICS FR2054
- COST MOBIEU [CA15126]
Intrinsic protein flexibility is crucial for the adaptability and recognition of complexes. This study reveals that the flexible region of the protein SET/TAF-I beta can activate PP2A by interacting with cytochrome c in a dynamic manner.
Intrinsic protein flexibility is of overwhelming relevance for intermolecular recognition and adaptability of highly dynamic ensemble of complexes, and the phenomenon is essential for the understanding of numerous biological processes. These conformational ensembles-encounter complexes-lack a unique organization, which prevents the determination of well-defined high resolution structures. This is the case for complexes involving the oncoprotein SET/template-activating factor-I beta (SET/TAF-I beta), a histone chaperone whose functions and interactions are significantly affected by its intrinsic structural plasticity. Besides its role in chromatin remodeling, SET/TAF-I beta is an inhibitor of protein phosphatase 2A (PP2A), which is a key phosphatase counteracting transcription and signaling events controlling the activity of DNA damage response (DDR) mediators. During DDR, SET/TAF-I beta is sequestered by cytochrome c (Cc) upon migration of the hemeprotein from mitochondria to the cell nucleus. Here, we report that the nuclear SET/TAF-I beta:Cc polyconformational ensemble is able to activate PP2A. In particular, the N-end folded, globular region of SET/TAF-I beta (a.k.a. SET/TAF-I beta Delta C)-which exhibits an unexpected, intrinsically highly dynamic behavior-is sufficient to be recognized by Cc in a diffuse encounter manner. Cc-mediated blocking of PP2A inhibition is deciphered using an integrated structural and computational approach,
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