Abstract
Reversible cysteine oxidation plays an essential role in redox signaling by reversibly altering protein structure and function. Cysteine oxidation may lead to intra- and intermolecular disulfide formation, and the latter can drastically stabilize protein–protein interactions in a more oxidizing milieu. The activity of the tumor suppressor p53 is regulated at multiple levels, including various post-translational modification (PTM) and protein–protein interactions. In the past few decades, p53 has been shown to be a redox-sensitive protein, and undergoes reversible cysteine oxidation both in vitro and in vivo. It is not clear, however, whether p53 also forms intermolecular disulfides with interacting proteins and whether these redox-dependent interactions contribute to the regulation of p53. In the present study, by combining (co-)immunoprecipitation, quantitative mass spectrometry and Western blot we found that p53 forms disulfide-dependent interactions with several proteins under oxidizing conditions. Cysteine 277 is required for most of the disulfide-dependent interactions of p53, including those with 14-3-3θ and 53BP1. These interaction partners may play a role in fine-tuning p53 activity under oxidizing conditions.
Highlights
These programs contribute to the maintenance of genome integrity and protect the organism from over-proliferation of cells that carry oncogenic mutations. p53 stabilization and function are controlled by post-translational modifications (PTMs) such as phosphorylation, acetylation, ubiquitination and methylation that may vary depending on the type of stress [2]
We propose that the observed covalent interactions with p53 could be involved in fine tuning the spatiotemporal p53 response by stabilization otherwise weak protein–protein interactions under oxidizing conditions
We provide evidence that cysteine oxidation of p53 leads to the formation of several intermolecular disulfide-dependent complexes, most of which depend on C277
Summary
P53 activation triggers cell cycle arrest and apoptosis, but is involved in cellular survival programs through the induction of DNA damage repair and metabolic regulation. These programs contribute to the maintenance of genome integrity and protect the organism from over-proliferation of cells that carry oncogenic mutations. A particular attractive mode of redox modification is the formation of intermolecular disulfides, because it can stabilize otherwise weak protein–protein interactions. In this way, protein function can be modified
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