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. 2011 Jan;20(1):131-9.
doi: 10.1002/pro.544.

Structure of Sir2Tm bound to a propionylated peptide

Poonam Bheda  1 , Jennifer T Wang, Jorge C Escalante-Semerena, Cynthia Wolberger
Affiliations

Structure of Sir2Tm bound to a propionylated peptide

Poonam Bheda et al. Protein Sci. 2011 Jan.

Abstract

Lysine propionylation is a recently identified post-translational modification that has been observed in proteins such as p53 and histones and is thought to play a role similar to acetylation in modulating protein activity. Members of the sirtuin family of deacetylases have been shown to have depropionylation activity, although the way in which the sirtuin catalytic site accommodates the bulkier propionyl group is not clear. We have determined the 1.8 Å structure of a Thermotoga maritima sirtuin, Sir2Tm, bound to a propionylated peptide derived from p53. A comparison with the structure of Sir2Tm bound to an acetylated peptide shows that hydrophobic residues in the active site shift to accommodate the bulkier propionyl group. Isothermal titration calorimetry data show that Sir2Tm binds propionylated substrates more tightly than acetylated substrates, but kinetic assays reveal that the catalytic rate of Sir2Tm deacylation of propionyl-lysine is slightly reduced to acetyl-lysine. These results serve to broaden our understanding of the newly identified propionyl-lysine modification and the ability of sirtuins to depropionylate, as well as deacetylate, substrates.

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Figures

Figure 1
Figure 1
Chemical structure of acetyl (left), propionyl (middle), and butyryl (right) modifications.
Figure 2
Figure 2
Deacylation activity of Sir2Tm. Activity is shown for acetylated (red) and propionylated (blue) p53 peptides. Rates of reaction were measured by an NAD+ consumption assay. The reactions were performed with 50 μg/mL Sir2Tm and 1 mM NAD+ for 15 min at 37°C. Concentration of the substrate peptides was varied from 12.5 μM to 1 mM.
Figure 3
Figure 3
Isothermal titration calorimetry of peptide binding. (a) Representative isothermal calorimetry titration of propionyl-lysine peptide binding to Sir2Tm at 25°C. Sir2Tm was titrated with injections of propionylated p53 peptide. (b) Representative isothermal calorimetry titration of acetyl-lysine peptide binding to Sir2Tm 25°C. (c) Change in heat capacity calculated based on temperature dependence of change in enthalpy of Sir2Tm binding to propionylated (blue) and acetylated (red) p53 peptides. The ΔCp values obtained for Sir2Tm binding were −318.8 ± 2.7 cal mol−1 K−1 for propionyl-lysine compared with −292.6 ± 3.8 cal mol−1 K−1 for acetyl-lysine.
Figure 4
Figure 4
Electron density maps showing region of peptide binding to Sir2Tm. (a) 2Fo-Fc stereo map (blue) contoured at 1σ of propionylated p53 peptide (yellow) bound to Sir2Tm (gray). (b) Simulated annealing omit map calculated with the propionyl moiety omitted. 2Fo-Fc map (purple) contoured at 1.5σ and Fo-Fc map (green) contoured at 3σ show well-defined positive density for the propionyl modification. (c) The positions of key Sir2Tm active site residues in complexes with propionylated (Sir2Tm teal, peptide yellow) and acetylated (Sir2Tm gray, peptide orange; PDB ID 2H2D) peptides.
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References

    1. Starai VJ, Celic I, Cole RN, Boeke JD, Escalante-Semerena JC. Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine. Science. 2002;298:2390–2392. - PubMed
    1. Chen Y, Sprung R, Tang Y, Ball H, Sangras B, Kim SC, Falck JR, Peng J, Gu W, Zhao Y. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol Cell Proteomics. 2007;6:812–819. - PMC - PubMed
    1. Garrity J, Gardner JG, Hawse W, Wolberger C, Escalante-Semerena JC. N-lysine propionylation controls the activity of propionyl-CoA synthetase. J Biol Chem. 2007;282:30239–30245. - PubMed
    1. Cheng Z, Tang Y, Chen Y, Kim S, Liu H, Li SS, Gu W, Zhao Y. Molecular characterization of propionyllysines in non-histone proteins. Mol Cell Proteomics. 2009;8:45–52. - PMC - PubMed
    1. Tanny JC, Moazed D. Coupling of histone deacetylation to NAD breakdown by the yeast silencing protein Sir2: evidence for acetyl transfer from substrate to an NAD breakdown product. Proc Natl Acad Sci USA. 2001;98:415–420. - PMC - PubMed

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