Targeting the Prion-like Aggregation of Mutant p53 to Combat Cancer

Abstract

Prion-like behavior of several amyloidogenic proteins has been demonstrated in recent years. Despite having functional roles in some cases, irregular aggregation can have devastating consequences. The most commonly known amyloid diseases are Alzheimer's, Parkinson's, and Transmissible Spongiform Encephalopathies (TSEs). The pathophysiology of prion-like diseases involves the structural transformation of wild-type (wt) proteins to transmissible forms that can convert healthy proteins, generating aggregates. The mutant form of tumor suppressor protein, p53, has recently been shown to exhibit prion-like properties. Within the context of p53 aggregation and the search for ways to avert it, this review emphasizes discoveries, approaches, and research from our laboratory and others. Although its standard functions are strongly connected to tumor suppression, p53 mutants and aggregates are involved in cancer progression. p53 aggregates are heterogeneous assemblies composed of amorphous aggregates, oligomers, and amyloid-like fibrils. Evidence of these structures in tumor tissues, the in vitro capability for p53 mutants to coaggregate with wt protein, and the detection of cell-to-cell transmission indicate that cancer has the basic characteristics of prion and prion-like diseases. Various approaches aim to restore p53 functions in cancer. Methods include the use of small-molecule and peptide stabilizers of mutant p53, zinc administration, gene therapy, alkylating and DNA intercalators, and blockage of p53-MDM2 interaction. A primary challenge in developing small-molecule inhibitors of p53 aggregation is the large number of p53 mutations. Another issue is the inability to recover p53 function by dissociating mature fibrils. Consequently, efforts have emerged to target the intermediate species of the aggregation reaction. Φ-value analysis has been used to characterize the kinetics of the early phases of p53 aggregation. Our experiments using high hydrostatic pressure (HHP) and chemical denaturants have helped to clarify excited conformers of p53 that are prone to aggregation. Molecular dynamics (MD) and phasor analysis of single Trp fluorescence signals point toward the presence of preamyloidogenic conformations of p53, which are not observed for p63 or p73. Exploring the features of competent preamyloidogenic states of wt and different p53 mutants may provide a framework for designing personalized drugs for the restoration of p53 function. Protection of backbone hydrogen bonds (BHBs) has been shown to be an important factor for the stability of amyloidogenic proteins and was employed to identify and stabilize the structural defect resulting from the p53 Y220C mutation. Using MD simulations, we compared BHB protection factors between p53 family members to determine the donor-acceptor pairs in p53 that exhibit lower protection. The identification of structurally vulnerable sites in p53 should provide new insights into rational designs that can rapidly be screened using our experimental methodology. Through continued and com...

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

“…These groups, including ours, have been working on discovering novel molecules that affect mutant p53 aggregates and have been attempting to obtain a deeper understanding of its aggregation process. We realize that p53 does not behave as a classic amyloid, forming arranged fibers with a unique pattern of organization, as discussed by Wang and Fersht (49) and Silva et al (48). p53 has different sites available for aggregation, which leads to less organized amyloid structures because of its variability and weakens any attempt to block only one aggregation-prone site.…”

Conformational flexibility of GRASP protein and its constituent PDZ subdomains reveals structural basis of its promiscuous interactome

“…For example, prion-forming sequences, which are especially enriched in asparagine, have been shown to promote molten globule-like structures, in which amyloid-nucleating contacts can be made [55,56]. Mutant forms of the tumor suppressor protein, p53, have recently been shown to behave as molten globules while exhibiting prion-like properties and, although its standard functions are strongly connected to tumor suppression, p53 mutants and aggregates are involved in cancer progression [57,58].…”

Conformational stability and dynamics of the cancer‐associated isoform Δ133p53β are modulated by p53 peptides and p53‐specific DNA

“…The destabilized p53 is likely to increase the solvent exposure of the hydrophobic core region, thus making it prone to aggregation (63). Experiments suggest that p53 aggregation can cause cancers (10,33,64,65). Recent experiments show that the hydrophobic region 251 ILTIITL 257 can trigger the aggregation of p53 (66).…”