Inhibition of the PP2A activity by the histone chaperone ANP32B is long-range allosterically regulated by respiratory cytochrome c

Redox Biology

Irene Díaz-Moreno¹  Rosa M. Ríos²  Miguel A. De la Rosa³  Maria P. Gavilan⁴  Adrián Velázquez-Campoy⁵  Antonio Díaz-Quintana⁶  Katiuska González-Arzola⁶  Francisco Rivero-Rodríguez⁶  Alejandro Velázquez-Cruz⁶ 

[1] Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029, Madrid, Spain;Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009, Zaragoza, Spain;Instituto de Investigación Sanitaria de Aragón (IIS Aragon), Zaragoza, Spain;Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, University of Seville, CSIC, University Pablo de Olavide, Avda. Américo Vespucio 24, Seville, 41092, Spain;Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSICBIFI,and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018, Zaragoza, Spain;Institute for Chemical Research (IIQ), Scientific Research Centre “Isla de La Cartuja” (cicCartuja), University of Seville, CSIC, Avda. Américo Vespucio 49, Seville, 41092, Spain;

关键词: Cytochrome c;    Histone chaperone;    Nuclear magnetic resonance;    Molecular dynamics;    Protein-protein interactions;   

DOI  :  

来源: DOAJ

【 摘 要 】

Repair of injured DNA relies on nucleosome dismantling by histone chaperones and de-phosphorylation events carried out by Protein Phosphatase 2A (PP2A). Typical histone chaperones are the Acidic leucine-rich Nuclear Phosphoprotein 32 family (ANP32) members, e.g. ANP32A, which is also a well-known PP2A inhibitor (a.k.a. I1PP2A). Here we report the novel interaction between the endogenous family member B—so-called ANP32B—and endogenous cytochrome c in cells undergoing camptothecin-induced DNA damage. Soon after DNA lesions but prior to caspase cascade activation, the hemeprotein translocates to the nucleus to target the Low Complexity Acidic Region (LCAR) of ANP32B; in a similar way, our group recently reported that the hemeprotein targets the acidic domain of SET/Template Activating Factor-Iβ (SET/TAF-Iβ), which is another histone chaperone and PP2A inhibitor (a.k.a. I2PP2A). The nucleosome assembly activity of ANP32B is indeed unaffected by cytochrome c binding. Like ANP32A, ANP32B inhibits PP2A activity and is thus herein referred to as I3PP2A. Our data demonstrates that ANP32B-dependent inhibition of PP2A is regulated by respiratory cytochrome c, which induces long-distance allosteric changes in the structured N-terminal domain of ANP32B upon binding to the C-terminal LCAR. In agreement with the reported role of PP2A in the DNA damage response, we propose a model wherein cytochrome c is translocated from the mitochondria into the nucleus upon DNA damage to modulate PP2A activity via its interaction with ANP32B.

【 授权许可】

Unknown