Mechanistic insight into the destabilization of p53TD tetramer by cancer-related R337H mutation: a molecular dynamics study

Abstract

The p53 protein is a tumor suppressor crucial for cell cycle and genome integrity. In a very large proportion of human cancers, p53 is frequently inactivated by mutations located in...

How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain?

“…R337H is the most common mutation in the TD, and it is associated with Li-Fraumeni syndrome, which gives rise to several types of cancer. Due to its correlation with cancer, this mutant has been studied and characterised by several groups [ 55 , 56 , 57 , 58 , 59 ], as well as in yeast [ 15 ] and mouse [ 60 ] models. Di Giammarino and co-workers reported that R337H strongly destabilises the tetramer and that its stability is pH-dependent, i.e., tetramer stability is partially recovered by decreasing the pH to acidic values [ 55 ].…”

Recognition between CD147 and cyclophilin A deciphered by accelerated molecular dynamics simulations

“…This method has been widely used to analyze MD trajectories. [66][67][68] The aMD simulations were reweighted using the PyReweighting toolkit 69 to calculate the 2D PMF profiles of PC1 and PC2 in three CD147-CypA systems (Fig. S2b, d and f, ESI †).…”

Oncogenic R248W mutation induced conformational perturbation of the p53 core domain and the structural protection by proteomimetic amyloid inhibitor ADH-6

“…Moreover, ADH-6 inhibits the aggregation of R248W p53 in human cancer cells, restoring the transcriptional activity of p53, leading to cell cycle arrest and apoptosis. 19 Molecular dynamics (MD) simulations have been extensively employed to investigate the conformational properties of different domains of the p53 protein and its mutants, 41,42,[63][64][65][66][67][68][69] as well as the interactions between p53 protein domains and small molecules, 70 short peptides, 71 and other proteins. [72][73][74][75] In spite of experimental and computational studies, it remains mostly unknown how the R248W mutation induces destabilization of R248W p53C and how ADH-6 stabilizes R248W p53C.…”