PP2A is activated by cytochrome c upon formation of a diffuse encounter complex with SET/TAF-Iβ - Aix-Marseille Université Access content directly
Journal Articles Computational and Structural Biotechnology Journal Year : 2022

PP2A is activated by cytochrome c upon formation of a diffuse encounter complex with SET/TAF-Iβ

Abstract

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-Iβ (SET/TAF-Iβ), a histone chaperone whose functions and interactions are significantly affected by its intrinsic structural plasticity. Besides its role in chromatin remodeling, SET/TAF-Iβ 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-Iβ 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-Iβ:Cc polyconformational ensemble is able to activate PP2A. In particular, the N-end folded, globular region of SET/TAF-Iβ (a.k.a. SET/TAF-Iβ ΔC)-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, combining small-angle X-ray scattering, electron paramagnetic resonance, nuclear magnetic resonance, calorimetry and molecular dynamics simulations.
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Dates and versions

hal-03965171 , version 1 (31-01-2023)

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Attribution - NonCommercial - NoDerivatives

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Miguel Á. Casado-Combreras, Francisco Rivero-Rodríguez, Carlos A Elena-Real, Dmitry Molodenskiy, Antonio Díaz-Quintana, et al.. PP2A is activated by cytochrome c upon formation of a diffuse encounter complex with SET/TAF-Iβ. Computational and Structural Biotechnology Journal, 2022, 20, pp.3695-3707. ⟨10.1016/j.csbj.2022.07.009⟩. ⟨hal-03965171⟩
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