Kinetic mechanism of p53 oncogenic mutant aggregation and its inhibition.

ABSTRACT: Aggregation of destabilized mutants of the tumor suppressor p53 is a major route for its loss of activity. In order to assay drugs that inhibit aggregation of p53, we established the basic kinetics of aggregation of its core domain, using the mutant Y220C that has a mutation-induced, druggable cavity. Aggregation monitored by light scattering followed lag kinetics. Electron microscopy revealed the formation of small aggregates that subsequently grew to larger amorphous aggregates. The kinetics of aggregation produced surprising results: progress curves followed either by the binding of Thioflavin T or the fluorescence of the protein at 340 nm fitted well to simple two-step sequential first-order lag kinetics with rate constants k(1) and k(2) that were independent of protein concentration,

SUBMITTER: Wilcken R 

PROVIDER: S-EPMC3427094 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature