Conclusion

Abstract

p53 tetramer formation is essential for DNA binding, post-translational modification, and protein–protein interaction. To clarify the threshold for dysfunction of p53 in terms of the destabilization of p53’s tetrameric structure, this study focused on the effects of tumor-associated mutations in the tetramerization domain on tetrameric structure and function. Based on a structure–function analysis of mutant p53, we also demonstrated functional regulation of p53 via the control of tetramer formation. Furthermore, we demonstrated that tumor-associated mutations in the tetramerization domain destabilized the tetrameric structure and significantly decreased the tetramer fraction in the nucleus at endogenous p53 levels. Indeed, the threshold for loss of tumor suppressor activity of p53 in terms of disruption of the tetrameric structure is suggested to be extremely low. In addition, relatively small changes in tetramer formation, induced by the stabilization or inhibition of homo-tetramerization, could control p53 function.