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Abstract
P53 Phase separation is crucial towards amyloid aggregation and p63 and p73 have enhanced expression in tumors. This study examines the phase behaviors of p53, p63, and p73. Here we show that unlike the DNA-binding domain of p53 (p53C), the p63C and p73C undergo phase separation, but do not form amyloids under physiological temperatures. Wild-type and mutant p53C form droplets at 4°C and aggregates at 37 °C with amyloid properties. Mutant p53C promotes amyloid-like states in p63C and p73C, recruiting them into membraneless organelles. Amyloid conversion is supported by thioflavin T and Congo red binding, increased light scattering, and circular dichroism. Full-length mutant p53 and p63C (or p73C) co-transfection shows reduced fluorescence recovery after photobleaching. Heparin inhibits the prion-like aggregation of p63C and p73C induced by p53C. These findings highlight the role of p53 in initiating amyloid aggregation in p63 and p73, opening avenues for targeting prion-like conversion in cancer therapy.
Phase separation of p53 is crucial in its progression towards amyloid aggregation, while its paralogous forms p63 and p73 have enhanced expression in tumors but reduced aggregation propensity. Here, the authors report the prion-like aggregation of p63 and p73 mediated by p53 and outline that this process can be inhibited by heparin.
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1 Federal University of Rio de Janeiro, Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X)
2 Federal University of Rio de Janeiro, National Center for Structural Biology and Bioimaging (CENABIO), Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X)
3 Federal University of Rio de Janeiro, Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X); Federal University of Rio de Janeiro, National Center for Structural Biology and Bioimaging (CENABIO), Rio de Janeiro, Brazil (GRID:grid.8536.8) (ISNI:0000 0001 2294 473X)