Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants.

ABSTRACT: Missense mutations in the p53 DNA-binding domain (DBD) contribute to half of new cancer cases annually. Here we present a thermodynamic model that quantifies and links the major pathways by which mutations inactivate p53. We find that DBD possesses two unusual properties-one of the highest zinc affinities of any eukaryotic protein and extreme instability in the absence of zinc-which are predicted to poise p53 on the cusp of folding/unfolding in the cell, with a major determinant being available zinc concentration. We analyze the 20 most common tumorigenic p53 mutations and find that 80% impair zinc affinity, thermodynamic stability, or both. Biophysical, cell-based, and murine xenograft experiments demonstrate that a synthetic zinc metallochaperone rescues not only mutations that decrease

SUBMITTER: Blanden AR 

PROVIDER: S-EPMC7728444 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature