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Characterization of full-length p53 aggregates and their kinetics of formation

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Peer-reviewed

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Abstract

Mutations in the TP53 gene are common in cancer with the R248Q missense mutation conferring an increased propensity to aggregate. Previous p53 aggregation studies showed that at micromolar concentrations, protein unfolding to produce aggregation-prone species, is the rate-determining step. Here we show that at physiological concentrations, aggregation kinetics of insect cell-derived full-length wild-type p53 and p53R248Q are determined by a nucleation-growth model, rather than formation of aggregation-prone monomeric species. Self-seeding, but not cross-seeding, increases aggregation rate, confirming the aggregation process as rate determining. p53R248Q displays enhanced aggregation propensity due to decreased solubility and increased aggregation rate, forming greater numbers of larger amorphous aggregates that disrupt lipid bilayers and invokes an inflammatory response. These results suggest that p53 aggregation can occur under physiological conditions, a rate enhanced by R248Q mutation, and that aggregates formed can cause membrane damage and inflammation which may influence tumourigenesis

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Biophysical Journal

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0006-3495

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Biophysical Society

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Sponsorship
Cancer Research UK (C55296/A26605)
This work was funded by the CRUK Cambridge Centre Early Detection Programme Pump Priming Award to S.R and D.K (RG80668) and the Multidisciplinary Project Award (26605). D.K. holds a Royal Society Professorship.