In 1972, the Weber statement, “The multiplicity of interactions and the variety of effects that follow from them show that multimer proteins are unlikely to be limited to a minimal number of allowed conformations,” first addressed the dynamic nature of proteins. This idea serves as a foundation for understanding why several macromolecules, such as p53, exhibit the properties of a molecular chameleon. Functionally competent states comprise a myriad of p53 three-dimensional arrangements depending on the stimuli. For instance, the interaction of p53 with nuclear components could induce liquid–liquid phase separation (LLPS) and the formation of membraneless organelles. The functional or deleterious role of p53 in liquid droplets is still unclear. Functional aspects display p53 interconverting between droplets and tetramer with its functional abilities maintained. In contrast, the aberrant phase separation is likely to fuel the aggregation path, usually associated with the onset and progression of age-related neurodegenerative diseases and cancer. Here, we gathered the most relevant aspects that lead p53 to phase separation and the resulting structural effects, attempting to understand p53’s functional and disease-relevant processes. Aberrant phase separation and aggregation of mutant p53 have become important therapeutic targets against cancer.

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