Differences in the transactivation domains of p53 family members: a computational study.
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.
Bioinformatics Institute (A-STAR), Matrix, Singapore. jagadeesh@bii.a-star.edu.sg
Jagadeesh N
JN
Mavinahalli
Arumugam
A
Madhumalar
Roger W
RW
Beuerman
David P
DP
Lane
Chandra
C
Verma
D000595:Amino Acid Sequence; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D013816:Thermodynamics; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050880:p300-CBP Transcription Factors; D051736:Proto-Oncogene Proteins c-mdm2