Tetramer formation of tumor suppressor protein p53: Structure, function, and applications

Abstract

Tetramer formation of p53 is essential for its tumor suppressor function. p53 not only acts as a tumor suppressor protein by inducing cell cycle arrest and apoptosis in response to genotoxic stress, but it also regulates other cellular processes, including autophagy, stem cell self-renewal, and reprogramming of differentiated cells into stem cells, immune system, and metastasis. More than 50% of human tumors have TP53 gene mutations, and most of them are missense mutations that presumably reduce tumor suppressor activity of p53. This review focuses on the role of the tetramerization (oligomerization), which is modulated by the protein concentration of p53, posttranslational modifications, and/or interactions with its binding proteins, in regulating the tumor suppressor function of p53. Functional control of p53 by stabilizing or inhibiting oligomer formation and its bio-applications are also discussed. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 598-612, 2016.

Structural visualization of the p53/RNA polymerase II assembly

“…We therefore cannot rule out that oligomeric p53 (e.g., dimer) could be present in our p53/Pol II structure. Thus far, limited evidence has been provided regarding the oligomeric status of p53 when bound to its interactors (Kamada et al 2016). Therefore, it remains an open question whether the tetrameric form of p53 exclusively binds to its interacting factors.…”

Genomic profiling of multiple sequentially acquired tumor metastatic sites from an “exceptional responder” lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response

“…In fact, 27 out of 35 WGS reads were of the mutated form, suggesting that this tumor suppressor may have been biallelically mutated in this tumor. Somatic mutations within the TP53 tetramirization domain are rare in cancer (Chene 2001; Kamada et al 2015). However, TP53 tetramerization is essential for DNA binding and transcriptional activity, as well as for a variety of its posttranslational modifications and proteasome-mediated degradation (Pietenpol et al 1994; Kawaguchi et al 2005; Itahana et al 2009; Lang et al 2014).…”

p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept

“…Besides its importance for the site-specific DNA binding [151], homo-tetramer formation of p53, which is mediated by the C-terminal tetramerization domain of this protein, is essential for protein–protein interactions and may play a role in posttranslational modifications [152]. One should keep in mind that tetramerization can be affected by PTMs, alternative splicing, or cancer-related mutations, and various hetero-tetramers can be present, whose protomers could be wild-type or mutants of the canonical p53, or its alternatively spliced isoforms.…”