Cytochrome c prompts the recruitment of its nuclear partners SET/TAF-Iβ and NPM1 into biomolecular condensates
Miguel Á. Casado-Combreras,
Adrián Velázquez-Campoy,
Marlène Martinho,
Valérie Belle,
Miguel A. De la Rosa,
Irene Díaz-Moreno
Affiliations
Miguel Á. Casado-Combreras
Institute for Chemical Research (IIQ), Scientific Research Center “Isla de la Cartuja” (cicCartuja), University of Seville - CSIC, Seville, Spain
Adrián Velázquez-Campoy
Institute for Biocomputation and Physic of Complex Systems (BIFI), Joint Unit GBsC-CSIC-BIFI, University of Zaragoza, Zaragoza, Spain; Departament of Biochemistry and Molecular and Cellular Biology, University of Zaragoza, Zaragoza, Spain; Institute for Health Research Aragón (IIS Aragon), Zaragoza, Spain; Centre for Biomedical Research Network of Hepatic and Digestive Diseases (CIBERehd), Madrid, Spain
Marlène Martinho
Aix Marseille University, CNRS, BIP, Bioénergétique et Ingénierie des Protéines, IMM, IM2B, Marseille, France
Valérie Belle
Aix Marseille University, CNRS, BIP, Bioénergétique et Ingénierie des Protéines, IMM, IM2B, Marseille, France
Miguel A. De la Rosa
Institute for Chemical Research (IIQ), Scientific Research Center “Isla de la Cartuja” (cicCartuja), University of Seville - CSIC, Seville, Spain
Irene Díaz-Moreno
Institute for Chemical Research (IIQ), Scientific Research Center “Isla de la Cartuja” (cicCartuja), University of Seville - CSIC, Seville, Spain; Corresponding author
Summary: Compartmentalization of proteins by liquid-liquid phase separation (LLPS) is used by cells to control biochemical reactions spatially and temporally. Among them, the recruitment of proteins to DNA foci and nucleolar trafficking occur by biomolecular condensation. Within this frame, the oncoprotein SET/TAF-Iβ plays a key role in both chromatin remodeling and DNA damage response, as does nucleophosmin (NPM1) which indeed participates in nucleolar ribosome synthesis. Whereas phase separation by NPM1 is widely characterized, little is known about that undergone by SET/TAF-Iβ. Here, we show that SET/TAF-Iβ experiences phase separation together with respiratory cytochrome c (Cc), which translocates to the nucleus upon DNA damage. Here we report the molecular mechanisms governing Cc-induced phase separation of SET/TAF-Iβ and NPM1, where two lysine-rich clusters of Cc are essential to recognize molecular surfaces on both partners in a specific and coordinated manner. Cc thus emerges as a small, globular protein with sequence-encoded heterotypic phase-separation properties.
