PP2A is activated by cytochrome c upon formation of a diffuse encounter complex with SET/TAF-Iβ
|Casado Combreras, Miguel Ángel
Rivero Rodríguez, Francisco
Elena-Real, Carlos A.
Díaz Quintana, Antonio Jesús
González Arzola, Katiuska
Velázquez Campoy, Adrián
Rosa Acosta, Miguel Ángel de la
Díaz Moreno, Irene
|Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular
|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 ...
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.
|Ministerio de Ciencia e Innovación (MICIN). España
Junta de Andalucía
|Casado Combreras, M.Á., Rivero Rodríguez, F., Elena-Real, C.A., Molodenskiy, D., Díaz Quintana, A.J., Martinho, M.,...,Díaz Moreno, I. (2022). PP2A is activated by cytochrome c upon formation of a diffuse encounter complex with SET/TAF-Iβ. Computational and Structural Biotechnology Journal, 20, 3695-3707.