Proteins of the S100 family bind to the intrinsically disordered transactivation 
domain (TAD; residues 1-57) and C-terminus (residues 293-393) of the tumor 
suppressor p53. Both regions provide sites that are subject to posttranslational 
modifications, such as phosphorylation and acetylation, that can alter the 
affinity for interacting proteins such as p300 and MDM2. Here, we found that 
S100A1, S100A2, S100A4, S100A6, and S100B bound to two subdomains of the TAD 
(TAD1 and TAD2). Both subdomains were mandatory for high-affinity binding to 
S100 proteins. Phosphorylation of Ser and Thr residues increased the affinity 
for the p53 TAD. Conversely, acetylation and phosphorylation of the C-terminus 
of p53 decreased the affinity for S100A2 and S100B. In contrast, we found that 
nitrosylation of S100B caused a minor increase in binding to the p53 C-terminus, 
whereas binding to the TAD remained unaffected. As activation of p53 is usually 
accompanied by phosphorylation and acetylation at several sites, our results 
suggest that a shift in binding from the C-terminus in favor of the N-terminus 
occurs upon the modification of p53. We propose that binding to the p53 TAD 
might be involved in the stimulation of p53 activity by S100 proteins.