Liquid-liquid phase separation of polyectrolytes in biomolecular condensation and protein aggregation

Biomolecular condensates are unique structures that form through liquid-liquid phase separation, without the presence of a membrane. While they serve essential physiological roles, they can also undergo a solid-phase transition, leading to amyloid-like structures that contribute to degenerative diseases and cancer. We will present recent research on the formation of biomolecular condensates and protein aggregates in cancer and neurodegenerative diseases, with a particular focus on the p53 tumor suppressor and its paralogs. More than half of malignant tumors harbor mutations in the TP53 gene and will kill millions if new therapies are not developed. Here, we focus on the fact that p53 not only undergoes misfolding but also forms biomolecular condensates and aggregates comparable to amyloids formed by other proteins, thereby playing a crucial role in cancer development through loss-of-function (LoF), negative dominance (ND), and gain-of-function (GoF) mechanisms. Strikingly, as in the case of toxic amyloids in neurodegenerative diseases, the molecular mechanisms responsible for the GoF of mutant p53 still need to be understood entirely. However, we already know that different cofactors, such as nucleic acids and glycosaminoglycans, are at the crossroads between these two classes of diseases. Our recent studies highlight that mutant p53 can induce amyloid aggregation in its paralogs, p63 and p73, which typically do not form amyloids under physiological conditions. In the presence of mutant p53, however, p63 and p73 co-aggregate, a process that can be inhibited by heparin. These findings underscore the critical role of mutant p53 in promoting the pathological aggregation of p63 and p73, suggesting new therapeutic targets. Thus, phase transitions to solid-like amorphous and amyloid-like states of mutant p53 and other tumor suppressor emerge as promising targets for the development of novel diagnostic and therapeutic strategies against cancer. (Supported by funds from CNPq, FAPERJ, CAPES and FINEP).