Abstract
The tumour suppressor p53 is now known to be an ancient transcription factor that had already evolved interaction sites with its partner protein MDM2 at the dawn of multi-cellular eukaryotic animal life. The billion- year life history of the p53-MDM2 axis has permitted significant time for the proteins to integrate into a distinct range of cellular pathways including binding to hundreds of genomic promoters and regulatory protein-protein interactions with hundreds of distinct functions. This long age of p53 allows us to understand how the protein can regulate a range of functions such as energy generation of the cell, cell motility, genome integrity, virus infection, immune cell response, ageing, and oxidative stress. Due to this deep integration of p53 into the core of eukaryotic life, it is not surprising that the p53 pathway requires inactivation in order for human cancer cells to evade the normal growth controlling processes that have been shaped through evolution by natural selection. This review will focus on the emerging concepts in the protein science field that shed light on p53 protein evolution and function including the nature of thermodynamically unstable regulatory proteins and the growing realisation that the majority of protein-protein interactions in complex eukaryotic cells are driven by intrinsically unstructured and weakly interacting peptide motifs. These concepts help to explain how the vast number of dynamic and specific protein-protein interactions in the p53 pathway evolved, suggest how amino acid modifications like phosphorylation or acetylation in turn evolved to regulate dynamically the p53 interactome, and finally reveal therapeutic strategies for targeting the p53 interactome in human cancers.
Highlights
The tumour suppressor p53 is known to be an ancient transcription factor that had already evolved interaction sites with its partner protein murine double minute clone 2 (MDM2) at the dawn of multi-cellular eukaryotic animal life
A study on protein disorder from different kingdoms have shown that the extent of disorder can be as low as 3% in prokaryotes, over 15% in yeast, and over 50% in mammals [4]
We have described the emerging view of the linear or disordered domain in the formation of protein-protein interactions in eukaryotes and how this can impact on our understanding of the protein interaction landscape that captures p53
Summary
B Homo_sapiens Rattus_norvegicus Danio_renio Ciona_intestinalis_489 Ciona_intestinalis_419 Nematostella_vectensis_378 Trichoplax_adhaerens Nematostella_vectensis_369 Drosophila_melanogaster Monosiga_brevicollis Caenorhabditis_elegans. Identifying approaches that can capture the dynamic linear motif interactome of a target protein provides another avenue to build systems map of a protein Such screens have expanded on the potential number of interactors to hundreds and highlight the utility in approaches that capture weak but regulatory PPIs. The p53 and MDM2 axis form an evolutionary ancient prototype protein-protein interaction pair that exploits the intrinsically disordered motif of one protein and a peptide-binding pocket interface in another. As the drug discovery field is acknowledging ever more that proteinprotein interactions form an untapped landscape for therapeutic development [84], it is highly likely that other oncogenic protein-protein interactions between linear intrinsically disordered motifs of p53 and peptide binding pockets in target proteins will emerge into drug discovery programmes in the future. MDM2 MDM4 histone acetyltransferase p300 replication protein A 70 RNA polymerase II transcription factor B S100ββ Sirtuin 2 CREB-binding protein Cyclin A (-CDK2) 14-3-3 USP7 histone acetyltransferase GCN5 methyltransferase SET9 O-GlcNAcase methyltransferase SMYD2 DNA repair factor 53BP1 DNA repair factor 53BP1 SV40 large T-antigen P53 tetramerisation peptide
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