An acetyl-methyl switch drives a conformational change in p53

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Posttranslational modifications (PTMs) on p53 regulate its functions.
• The combinatorial effects of adjacent PTMs are less understood than individual modifications.

Purpose of the Study:

• To investigate the crosstalk between adjacent PTMs on p53.
• To elucidate the structural and functional consequences of dual PTMs on p53 cofactor binding.

Main Methods:

• X-ray crystallography (1.8 Å resolution) to determine the structure of 53BP1's tandem Tudor domain (TTD) with modified p53 peptide.
• Biochemical assays and nuclear magnetic resonance (NMR) analyses to study PTM effects on p53-TTD interactions.

Main Results:

• The crystal structure revealed a novel conformation of p53 peptide with adjacent acetylation (K381ac) and dimethylation (K382me2).
• This dual modification positions key residues for concurrent interaction with 53BP1 TTD, suggesting a modular binding mechanism.
• Other PTMs, such as phosphorylation, were shown to influence p53 association with TTD.

Conclusions:

• A novel PTM-driven conformational switch mechanism regulates p53 interactions.
• Understanding these adjacent PTMs is crucial for deciphering p53-dependent responses in DNA damage.
• This work provides insights into the modular design of PTM recognition by protein domains.