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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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Evolution of secondary structures of the peptide variants at position 25 along the simulation: (A) p53: L25F (B) p63: F25L (C) p73: S25F; Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil.
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Figure 7: Evolution of secondary structures of the peptide variants at position 25 along the simulation: (A) p53: L25F (B) p63: F25L (C) p73: S25F; Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil.

Mentions: It is clear (Figure 7A, Movie S7) that p53 is severely destabilized, apart from a transient period of helicity as the introduced F collapses against F19 (as seen in wild type p63). In contrast, we see that in p63, the helix is indeed propagated (Figure 7B, Movie S8) due to the F25L mutation including the formation of full length helical structures. The analogous mutation in P73 is S25F and this leads to rapid helix formation followed by its stability (Figure 7C, Movie S9).


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)

Evolution of secondary structures of the peptide variants at position 25 along the simulation: (A) p53: L25F (B) p63: F25L (C) p73: S25F; Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Evolution of secondary structures of the peptide variants at position 25 along the simulation: (A) p53: L25F (B) p63: F25L (C) p73: S25F; Colour code: purple, α-helix; red, π-helix; yellow, β-sheet; green, isolated bridge; cyan, turn; white, random coil.
Mentions: It is clear (Figure 7A, Movie S7) that p53 is severely destabilized, apart from a transient period of helicity as the introduced F collapses against F19 (as seen in wild type p63). In contrast, we see that in p63, the helix is indeed propagated (Figure 7B, Movie S8) due to the F25L mutation including the formation of full length helical structures. The analogous mutation in P73 is S25F and this leads to rapid helix formation followed by its stability (Figure 7C, Movie S9).

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