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<p>The NAD⁺-dependent deacetylase sirtuin 1 (Sirt1) is known to regulate the tumor suppressor p53 via deacetylation, but the structural basis of the protein-protein interaction between full-length p53 and Sirt1 has so far remained elusive. We apply an integrated approach, combining structural mass spectrometry (MS) with data-driven molecular docking, to study the interaction between human p53 and Sirt1. Sirt1 was found to bind exclusively to acetylated p53 forming complexes with a 1:1 stoichiometry, irrespectively of p53’s oligomeric state. The lysine residue at position 382 (K382) in p53 was identified as predominant acetylation site showing a selective Sirt1-dependent deacetylation at this position. Cross-linking mass spectrometry (XL-MS) provided valuable distance constraints between p53 and Sirt1. Specifically, cross-links created between p53-K382 / Sirt1-K427 and p53-K120 / Sirt1-K622 give hints on a highly flexible interface. Molecular docking was conducted based on the distance constraints imposed by the cross-links, positioning Sirt1 at the DNA-binding and tetramerization domains of p53. This gives a rationale for a steric exclusion of additional Sirt1 molecules binding to p53. We present the first structural model of the full-length p53:Sirt1 (1:1) complex, establishing a mechanistic framework that links p53 activity to its Sirt1-controlled acetylation status.</p>

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Revisiting the p53:Sirt1 interaction in light of controlling p53 acetylation levels

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Vishnupriya Pandey,
  • Frank Hause,
  • Claudio Iacobucci,
  • Christian H. Ihling,
  • Christian Tueting,
  • Panagiotis L. Kastritis,
  • Christian Arlt,
  • Andrea Sinz

摘要

The NAD⁺-dependent deacetylase sirtuin 1 (Sirt1) is known to regulate the tumor suppressor p53 via deacetylation, but the structural basis of the protein-protein interaction between full-length p53 and Sirt1 has so far remained elusive. We apply an integrated approach, combining structural mass spectrometry (MS) with data-driven molecular docking, to study the interaction between human p53 and Sirt1. Sirt1 was found to bind exclusively to acetylated p53 forming complexes with a 1:1 stoichiometry, irrespectively of p53’s oligomeric state. The lysine residue at position 382 (K382) in p53 was identified as predominant acetylation site showing a selective Sirt1-dependent deacetylation at this position. Cross-linking mass spectrometry (XL-MS) provided valuable distance constraints between p53 and Sirt1. Specifically, cross-links created between p53-K382 / Sirt1-K427 and p53-K120 / Sirt1-K622 give hints on a highly flexible interface. Molecular docking was conducted based on the distance constraints imposed by the cross-links, positioning Sirt1 at the DNA-binding and tetramerization domains of p53. This gives a rationale for a steric exclusion of additional Sirt1 molecules binding to p53. We present the first structural model of the full-length p53:Sirt1 (1:1) complex, establishing a mechanistic framework that links p53 activity to its Sirt1-controlled acetylation status.