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Differences in the transactivation domains of p53 family members: a computational study.

Mavinahalli JN, Madhumalar A, Beuerman RW, Lane DP, Verma C - BMC Genomics (2010)

Bottom Line: Folding simulation studies have been carried out to examine the propensity and stability of this region and are used to understand the differences between the family members with the ease of helix formation following the order p53 > p73 > p63.Differences in these interactions between the family members may partially account for the differential binding to, and regulation by, MDM2 (and MDMX).Phosphorylations of the peptides further modulate the stability of the helix and control associations with partner proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Institute (A-STAR), Matrix, Singapore. jagadeesh@bii.a-star.edu.sg

ABSTRACT
The N terminal transactivation domain of p53 is regulated by ligases and coactivator proteins. The functional conformation of this region appears to be an alpha helix which is necessary for its appropriate interactions with several proteins including MDM2 and p300. Folding simulation studies have been carried out to examine the propensity and stability of this region and are used to understand the differences between the family members with the ease of helix formation following the order p53 > p73 > p63. It is clear that hydrophobic clusters control the kinetics of helix formation, while electrostatic interactions control the thermodynamic stability of the helix. Differences in these interactions between the family members may partially account for the differential binding to, and regulation by, MDM2 (and MDMX). Phosphorylations of the peptides further modulate the stability of the helix and control associations with partner proteins.

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Folding pattern of p73 Evolution of secondary structures of the p73 peptides as a function of simulation time Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil. (B) Hydrogen bond statistics of the secondary structures averaged over 100 ns of simulations; the lifetime of hydrogen bonds in 5 ns windows is shown as: Space ( ) for 0-5%, dot (.) for 5-20%, dash (-) for 20-40%, o for 40-60%, x for 60-80%, star (*) for 80-95% and at (@) for 95 – 100%. (C) Cluster analysis of secondary structures in terms of RMSD as a function of simulation time; a representative structure (N-terminus in blue, C-terminus in red) from each cluster is shown with % of population;  colour code of the plot: red is helix, yellow is β-Sheet and green is random structure. Conserved residues F19, W23 and L26 are shown as sticks.
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Figure 3: Folding pattern of p73 Evolution of secondary structures of the p73 peptides as a function of simulation time Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil. (B) Hydrogen bond statistics of the secondary structures averaged over 100 ns of simulations; the lifetime of hydrogen bonds in 5 ns windows is shown as: Space ( ) for 0-5%, dot (.) for 5-20%, dash (-) for 20-40%, o for 40-60%, x for 60-80%, star (*) for 80-95% and at (@) for 95 – 100%. (C) Cluster analysis of secondary structures in terms of RMSD as a function of simulation time; a representative structure (N-terminus in blue, C-terminus in red) from each cluster is shown with % of population; colour code of the plot: red is helix, yellow is β-Sheet and green is random structure. Conserved residues F19, W23 and L26 are shown as sticks.

Mentions: Figure 3A shows that α-helix formation in p73 lies in-between that of p53 and p63. While the helix initially is stable only beyond residue H21 as in p63 (equivalent residue H21), we do find that around 50ns, it extends towards the N-terminal. What is clear is that once this helical state is reached, stability sets in. HB analysis (Figure 3B) shows only one backbone-backbone HB while the other two are side chain-backbone HBs. The occupancy of the backbone-backbone interaction is 18.4% (greater than the 11.8% seen in p63) and 11% between positions F19 and W23. Among the conformations sampled, helices occupy 45% (Figure 3C) and their stability lies in between that of p53 and p63. Clusters 1 and 2 represent disordered motifs.


Differences in the transactivation domains of p53 family members: a computational study.

Mavinahalli JN, Madhumalar A, Beuerman RW, Lane DP, Verma C - BMC Genomics (2010)

Folding pattern of p73 Evolution of secondary structures of the p73 peptides as a function of simulation time Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil. (B) Hydrogen bond statistics of the secondary structures averaged over 100 ns of simulations; the lifetime of hydrogen bonds in 5 ns windows is shown as: Space ( ) for 0-5%, dot (.) for 5-20%, dash (-) for 20-40%, o for 40-60%, x for 60-80%, star (*) for 80-95% and at (@) for 95 – 100%. (C) Cluster analysis of secondary structures in terms of RMSD as a function of simulation time; a representative structure (N-terminus in blue, C-terminus in red) from each cluster is shown with % of population;  colour code of the plot: red is helix, yellow is β-Sheet and green is random structure. Conserved residues F19, W23 and L26 are shown as sticks.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822533&req=5

Figure 3: Folding pattern of p73 Evolution of secondary structures of the p73 peptides as a function of simulation time Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil. (B) Hydrogen bond statistics of the secondary structures averaged over 100 ns of simulations; the lifetime of hydrogen bonds in 5 ns windows is shown as: Space ( ) for 0-5%, dot (.) for 5-20%, dash (-) for 20-40%, o for 40-60%, x for 60-80%, star (*) for 80-95% and at (@) for 95 – 100%. (C) Cluster analysis of secondary structures in terms of RMSD as a function of simulation time; a representative structure (N-terminus in blue, C-terminus in red) from each cluster is shown with % of population; colour code of the plot: red is helix, yellow is β-Sheet and green is random structure. Conserved residues F19, W23 and L26 are shown as sticks.
Mentions: Figure 3A shows that α-helix formation in p73 lies in-between that of p53 and p63. While the helix initially is stable only beyond residue H21 as in p63 (equivalent residue H21), we do find that around 50ns, it extends towards the N-terminal. What is clear is that once this helical state is reached, stability sets in. HB analysis (Figure 3B) shows only one backbone-backbone HB while the other two are side chain-backbone HBs. The occupancy of the backbone-backbone interaction is 18.4% (greater than the 11.8% seen in p63) and 11% between positions F19 and W23. Among the conformations sampled, helices occupy 45% (Figure 3C) and their stability lies in between that of p53 and p63. Clusters 1 and 2 represent disordered motifs.

Bottom Line: Folding simulation studies have been carried out to examine the propensity and stability of this region and are used to understand the differences between the family members with the ease of helix formation following the order p53 > p73 > p63.Differences in these interactions between the family members may partially account for the differential binding to, and regulation by, MDM2 (and MDMX).Phosphorylations of the peptides further modulate the stability of the helix and control associations with partner proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Institute (A-STAR), Matrix, Singapore. jagadeesh@bii.a-star.edu.sg

ABSTRACT
The N terminal transactivation domain of p53 is regulated by ligases and coactivator proteins. The functional conformation of this region appears to be an alpha helix which is necessary for its appropriate interactions with several proteins including MDM2 and p300. Folding simulation studies have been carried out to examine the propensity and stability of this region and are used to understand the differences between the family members with the ease of helix formation following the order p53 > p73 > p63. It is clear that hydrophobic clusters control the kinetics of helix formation, while electrostatic interactions control the thermodynamic stability of the helix. Differences in these interactions between the family members may partially account for the differential binding to, and regulation by, MDM2 (and MDMX). Phosphorylations of the peptides further modulate the stability of the helix and control associations with partner proteins.

Show MeSH