The alpha-helical FXXPhiPhi motif in p53: TAF interaction and discrimination by MDM2.

Abstract

Transcriptional activation domains share little sequence homology and generally lack folded structures in the absence of their targets, aspects that have rendered activation domains difficult to characterize. Here, a combination of biochemical and nuclear magnetic resonance experiments demonstrates that the activation domain of the tumor suppressor p53 has an FXXPhiPhi motif (F, Phe; X, any amino acids; Phi, hydrophobic residues) that folds into an alpha-helix upon binding to one of its targets, hTAF(II)31 (a human TFIID TATA box-binding protein-associated factor). MDM2, the cellular attenuator of p53, discriminates the FXXPhiPhi motif of p53 from those of NF-kappaB p65 and VP16 and specifically inhibits p53 activity. Our studies support the notion that the FXXPhiPhi sequence is a general alpha-helical recognition motif for hTAF(II)31 and provide insights into the mechanistic basis for regulation of p53 function.