First-order rate-determining aggregation mechanism of p53 and its implications.

ABSTRACT: Aggregation of p53 is initiated by first-order processes that generate an aggregation-prone state with parallel pathways of major or partial unfolding. Here, we elaborate the mechanism and explore its consequences, beginning with the core domain and extending to the full-length p53 mutant Y220C. Production of large light-scattering particles was slower than formation of the Thioflavin T-binding state and simultaneous depletion of monomer. EDTA removes Zn(2+) to generate apo-p53, which aggregated faster than holo-p53. Apo-Y220C also aggregated by both partial and major unfolding. Apo-p53 was not an obligatory intermediate in the aggregation of holo-p53, but affords a parallel pathway that may be relevant to oncogenic mutants with impaired Zn(2+) binding. Full-length tetrameric Y220C formed

SUBMITTER: Wang G 

PROVIDER: S-EPMC3427100 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature