The alpha-helical FXX Phi Phi motif in p53: TAF interaction and discrimination by MDM2

Transcriptional activation domains share little sequence homology and gener ally lack folded structures in the absence of their targets, aspects that h ave rendered activation domains difficult to characterize. Here, a combinat ion of biochemical and nuclear magnetic resonance experiments demonstrates that the activation domain of the tumor suppressor p53 has an FXX Phi Phi m otif (F, Phe; X, any amino acids; Phi, hydrophobic residues) that folds int o an alpha-helix upon binding to one of its targets, hTAF(II)31 (a human TF IID TATA box-binding protein-associated factor). MDM2, the cellular attenua tor of p53, discriminates the FXX Phi Phi motif of p53 from those of NF-kap pa B p65 and VP16 and specifically inhibits p53 activity. Our studies suppo rt the notion that the FXX Phi Phi, sequence is a general alpha-helical rec ognition motif for hTAF(II)31 and provide insights into the mechanistic bas is for regulation of p53 function.