Article

Interaction between the transactivation domain of p53 and PC4 exemplifies acidic activation domains as single-stranded DNA mimics.

MRC Centre for Protein Engineering, Cambridge, United Kingdom.
Journal of Biological Chemistry (impact factor: 4.77). 07/2009; 284(32):21728-37. DOI:10.1074/jbc.M109.006429 pp.21728-37
Source: PubMed

ABSTRACT The tumor suppressor p53 regulates cell cycle arrest and apoptosis by transactivating several genes that are critical for these processes. The transcriptional activity of p53 is often regulated by post-translational modifications and its interactions with various transcriptional coactivators. Here we report a physical interaction between the N-terminal transactivation domain (TAD) of p53 and the C-terminal DNA-binding domain of positive cofactor 4 (PC4(CTD)). Using NMR spectroscopy, we showed that residues 35-57 (TAD2) interact with PC4. (15)N,(1)H HSQC and fluorescence competition experiments indicated that TAD binds to the DNA-binding site of PC4. Hepta-phosphorylation of the TAD peptide increased its binding affinity. Computer modeling of the p53N-PC4 complex revealed several important interactions that are reminiscent of those in the single-stranded DNA-PC4 complex. The ubiquitous nature of the acidic transactivation domain of p53 in mediating interactions with several transcription cofactors is also manifested as a DNA mimetic.

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Keywords

acidic transactivation domain
 
apoptosis
 
binding affinity
 
critical
 
DNA mimetic
 
fluorescence competition experiments
 
interactions
 
mediating interactions
 
N-terminal transactivation domain
 
NMR spectroscopy
 
p53N-PC4 complex
 
positive cofactor 4
 
single-stranded DNA-PC4 complex
 
TAD
 
TAD binds
 
TAD peptide
 
TAD2
 
transcriptional activity
 
tumor suppressor p53 regulates cell cycle arrest
 
various transcriptional coactivators