A novel mutation (G389E) in p53 “extreme C‐terminus”

Abstract

The human tumor suppressor protein p53 consists of several functional domains, including an N‐terminal activation domain, a DNA‐binding core domain and C‐terminal tetramerization and basic regions. The basic region (residues 367–393), termed the “extreme C‐terminus”, is a negative regulatory domain whose post‐translational phosphorylation and acetylation occurs in vivo and activates the tumor suppressor. A novel mutation (G389E) in the p53 “extreme C‐terminus” was identified in a patient with congenital adrenal hyperplasia (CAH). This study describes experimental and computational chemistry studies of wild type and mutant p53 “extreme C‐terminus” to gain insights into the structural changes which may occur upon G389E mutation and to investigate the molecular basis of the desease. Site‐directed mutagenesis experiments followed by in vitro protein expression, supported by molecular dynamics trajectories, outline the effect of the mutation on the phosphorylation sites which are clustered within the p53 “extreme C‐terminus” and the importance of intermolecular interactions in biological systems.