Intrinsic aggregation propensity of the p63 and p73 TI domains correlates with p53R175H interaction and suggests further significance of aggregation events in the p53 family

Abstract

The high percentage of p53 missense mutations found in cancer has been attributed to mutant acquired oncogenic gain of functions. Different aspects of these tumour-promoting functions are caused by repression of the transcriptional activity of p53 family members p63 and p73. A subset of frequently occurring p53 mutations results in thermodynamic destabilisation of the DNA-binding domain (DBD) rendering this domain highly unstable. These conformational mutants (such as p53R175H) have been suggested to directly bind to p63 and p73 via a co-aggregation mechanism mediated by their DBDs. Although the DBDs of p63 and p73 are in fact not sufficient for the interaction as shown previously, we demonstrate here that the transactivation inhibitory (TI) domains within the α-isoform-specific C termini of p63 and p73 are essential for binding to p53R175H. Hence, the closed dimeric conformation of inactive TAp63α that renders the TI domain inaccessible prevents efficient interaction. We further show that binding to p53R175H correlates with an intrinsic aggregation propensity of the tetrameric α-isoforms conferred by an openly accessible TI domain again supporting interaction via a co-aggregation mechanism.

p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells

“…Finally, PRIMA-1 has been suggested to release p73 The mutant p53 amyloid state is cleared by PRIMA-1 bound to mutant p53 (55). This might have additional effects on attenuating the gain-of-function effects of mutant p53 aggregates that interact with p73 (8,17,18). The effects of MQ on cellular proteins other than mutant p53 are related to the GSH and thioredoxin reductase system.…”

“…Gain-of-function (GoF) 4 effects, including increased invasion, altered migration (12,13), and drug resistance, have been reported for several mutants (14 -16). GoF effects have also been related to mutant p53 aggregation and its interaction with other proteins, such as the paralogous p63 and p73 proteins (8,11,(17)(18)(19).…”

Do Mutations Turn p53 into an Oncogene?

“…On the contrary, the conformational mutant p53R175H has been shown to aggregate to the family members p63 and p73, through an interaction that involves its DNA binding domain (DBD) and the C-terminal transactivation inhibitory (TI) domain of both p63 and p73 α-isoforms. Supporting this hypothesis, the TAp63α that in normal conditions acquires a closed conformation in which the TI domain is inaccessible, does not interact with p53R175H [84]. Through this co-aggregation mechanism, mutant p53 proteins may exert a dominant negative effect on p63 and p73, inhibiting their functions [85][86][87].…”

Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine

“…Notably, TP53 mutations and polymorphisms are often associated with the emergence of oncogenic "gain-of-function" activities by the protein product, which further contribute to cancer development. For example, the expression of mutant forms of p53 (missense mutations) affects cellular motility and invasion through several pathways, often involving the other members of the p53 family [70][71][72][73][74][75]. These evidences are derived from both somatic mutations and rare inherited mutations occurring in the Li-Fraumeni cancer syndrome [66].…”