How does p53 work? Regulation by the intrinsically disordered domains.

Abstract

Defects in the tumor suppressor protein p53 are found in the majority of cancers. The p53 protein (393 amino acids long) contains the folded DNA-binding domain (DBD) and tetramerization domain (TET), with the remainder of the sequence being intrinsically disordered. Since cancer-causing mutations occur primarily in the DBD, this has been the focus of most of the research on p53. However, recent reports show that the disordered N-terminal activation domain (NTAD) and C-terminal regulatory domain (CTD) function synergistically with the DBD to regulate p53 activity. We propose a mechanistic model in which intermolecular and intramolecular interactions of the disordered regions, modulated by post-translational modifications, perform a central role in the regulation and activation of p53 in response to cellular stress.