Evolutionary history of the p53 family DNA-binding domain: insights from an Alvinella pompejana homolog

Qiang Zhang,Bruno Baron,Thierry Soussi,Alon Senitzki,Dimitrios-Ilias Balourdas,Andreas C Joerger,Tali E Haran,Klas G Wiman

doi:10.1038/s41419-022-04653-8

Abstract

The extremophile Alvinella pompejana, an annelid worm living on the edge of hydrothermal vents in the Pacific Ocean, is an excellent model system for studying factors that govern protein stability. Low intrinsic stability is a crucial factor for the susceptibility of the transcription factor p53 to inactivating mutations in human cancer. Understanding its molecular basis may facilitate the design of novel therapeutic strategies targeting mutant p53. By analyzing expressed sequence tag (EST) data, we discovered a p53 family gene in A. pompejana. Protein crystallography and biophysical studies showed that it has a p53/p63-like DNA-binding domain (DBD) that is more thermostable than all vertebrate p53 DBDs tested so far, but not as stable as that of human p63. We also identified features associated with its increased thermostability. In addition, the A. pompejana homolog shares DNA-binding properties with human p53 family DBDs, despite its evolutionary distance, consistent with a potential role in maintaining genome integrity. Through extensive structural and phylogenetic analyses, we could further trace key evolutionary events that shaped the structure, stability, and function of the p53 family DBD over time, leading to a potent but vulnerable tumor suppressor in humans.

Highlights

The tumor suppressor p53 is an ideal paradigm for studying the effect of disease mutations and principles of protein evolution
Phylogenetic and structural analysis of the A. pompejana p53 homolog We performed a BLAST search of the A. pompejana expressed sequence tag (EST) database of the Max Planck Institute for Developmental Biology, Tübingen, Germany [36] to search for p53 family proteins and obtained a hit for a transcript containing a p53/p63-like DNAbinding domain (DBD) (N72937)
We were further able to show that the A. pompejana DBD has a much higher thermostability than the DBD of most vertebrate p53 variants, but is not as stable as that of human p63, which may be surprising at first glance

Summary

Introduction

The tumor suppressor p53 is an ideal paradigm for studying the effect of disease mutations and principles of protein evolution. Upon cellular stress, such as DNA damage or oxidative stress, p53 induces transcription of target genes triggering cell-cycle arrest and DNA repair, or apoptosis if the DNA damage is beyond repair [1, 2]. Besides these classical functions, p53 controls many other cellular processes, including senescence, angiogenesis, metabolism, and stemness [1, 2]. Understanding the structure of p53, the factors that govern its stability, and how it responds to mutation is essential for the development of mutant p53 rescue drugs

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Conclusion