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The structural basis of sirtuin substrate affinity.

Michael S Cosgrove1, Katherine Bever, Jose L Avalos

  • 1Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.

Biochemistry
|June 14, 2006
PubMed
Summary
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Sirtuins are enzymes that remove acetyl groups from proteins. This study reveals how specific amino acid positions in peptide substrates are key for sirtuin enzyme binding and recognition.

Area of Science:

  • Biochemistry
  • Enzymology
  • Structural Biology

Background:

  • Sirtuins are NAD+-dependent deacetylases with crucial cellular roles.
  • Understanding sirtuin substrate specificity is vital for deciphering their functions.
  • Limited structural data exists on how sirtuins differentiate between various substrates.

Purpose of the Study:

  • To systematically analyze the structural and thermodynamic basis of sirtuin-peptide interactions.
  • To investigate the role of specific peptide residues in substrate binding by sirtuins.
  • To develop a model for predicting sirtuin substrates.

Main Methods:

  • X-ray crystallography to determine the structures of Sir2Tm bound to various peptides and PPG.
  • Isothermal titration calorimetry (ITC) to quantify binding affinities.

Related Experiment Videos

  • Site-directed mutagenesis to probe the role of key residues in substrate recognition.

    • Main Results:

    • Five crystal structures of Sir2Tm were determined, including complexes with p53, histone-derived peptides, and PPG.
    • Novel complementary side chain interactions were observed at peptide positions -1 and +2.
    • ITC data confirmed the significant contribution of residues at positions -1 and +2 to binding affinity.

    Conclusions:

    • Peptide residues at positions -1 and +2 are critical determinants of sirtuin substrate binding.
    • A structural and thermodynamic model for sirtuin substrate recognition has been established.
    • This model can guide the identification of novel sirtuin substrates.