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Acetylation of lysine 120 of p53 endows DNA-binding specificity at effective physiological salt concentration.

Arbely E, Natan E, Brandt T, Allen MD, Veprintsev DB, Robinson CV, Chin JW, Joerger AC, Fersht AR
Proc Natl Acad Sci U S A 108 8251-6 (2011)
Cited: 65 times
EuropePMC logo PMID: 21525412

Abstract

Lys120 in the DNA-binding domain (DBD) of p53 becomes acetylated in response to DNA damage. But, the role and effects of acetylation are obscure. We prepared p53 specifically acetylated at Lys120, AcK120p53, by in vivo incorporation of acetylated lysine to study biophysical and structural consequences of acetylation that may shed light on its biological role. Acetylation had no affect on the overall crystal structure of the DBD at 1.9-Å resolution, but significantly altered the effects of salt concentration on specificity of DNA binding. p53 binds DNA randomly in vitro at effective physiological salt concentration and does not bind specifically to DNA or distinguish among its different response elements until higher salt concentrations. But, on acetylation, AcK120p53 exhibited specific DNA binding and discriminated among response elements at effective physiological salt concentration. AcK120p53 and p53 had the highest affinity to the same DNA sequence, although acetylation reduced the importance of the consensus C and G at positions 4 and 7, respectively. Mass spectrometry of p53 and AcK120p53 DBDs bound to DNA showed they preferentially segregated into complexes that were either DNA(p53DBD)(4) or DNA(AcK120DBD)(4), indicating that the different DBDs prefer different quaternary structures. These results are consistent with electron microscopy observations that p53 binds to nonspecific DNA in different, relaxed, quaternary states from those bound to specific sequences. Evidence is accumulating that p53 can be sequestered by random DNA, and target search requires acetylation of Lys120 and/or interaction with other factors to impose specificity of binding via modulating changes in quaternary structure.

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  3. Acetylation of lysine 120 of p53 endows DNA-binding specificity at effective physiological salt concentration. Arbely E, Natan E, Brandt T, Allen MD, Veprintsev DB, Robinson CV, Chin JW, Joerger AC, Fersht AR. Proc Natl Acad Sci U S A 108 8251-8256 (2011)


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  2. The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches. Joerger AC, Fersht AR. Annu Rev Biochem 85 375-404 (2016)
  3. Pyrrolysyl-tRNA synthetase: an ordinary enzyme but an outstanding genetic code expansion tool. Wan W, Tharp JM, Liu WR. Biochim Biophys Acta 1844 1059-1070 (2014)
  4. p53 Acetylation: Regulation and Consequences. Reed SM, Quelle DE. Cancers (Basel) 7 30-69 (2014)
  5. Designer proteins: applications of genetic code expansion in cell biology. Davis L, Chin JW. Nat Rev Mol Cell Biol 13 168-182 (2012)
  6. Protein lysine acylation and cysteine succination by intermediates of energy metabolism. Lin H, Su X, He B. ACS Chem Biol 7 947-960 (2012)
  7. Protein Acetylation and Its Role in Bacterial Virulence. Ren J, Sang Y, Lu J, Yao YF. Trends Microbiol 25 768-779 (2017)
  8. Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy. Wanior M, Krämer A, Knapp S, Joerger AC. Oncogene 40 3637-3654 (2021)
  9. Structural Insights Into TDP-43 and Effects of Post-translational Modifications. François-Moutal L, Perez-Miller S, Scott DD, Miranda VG, Mollasalehi N, Khanna M. Front Mol Neurosci 12 301 (2019)
  10. Biological applications of expanded genetic codes. Li X, Liu CC. Chembiochem 15 2335-2341 (2014)
  11. Regulation of metabolism by mitochondrial enzyme acetylation in cardiac ischemia-reperfusion injury. Herr DJ, Singh T, Dhammu T, Menick DR. Biochim Biophys Acta Mol Basis Dis 1866 165728 (2020)
  12. Genetic code expansion as a tool to study regulatory processes of transcription. Schmidt MJ, Summerer D. Front Chem 2 7 (2014)
  13. Functional analysis of protein post-translational modifications using genetic codon expansion. Peng T, Das T, Ding K, Hang HC. Protein Sci 32 e4618 (2023)
  14. Engineering Pyrrolysine Systems for Genetic Code Expansion and Reprogramming. Dunkelmann DL, Chin JW. Chem Rev 124 11008-11062 (2024)

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