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Papers In Press, published online ahead of print September 13, 2005
Department of Protein Analysis and Design Laboratory, Korea Research Institute of Bioscience and Biotechnology, Daejon, Yusong
Corresponding Author: khhan600{at}kribb.re.kr
Mdm2 is a cellular antagonist of p53 that keeps a balanced cellular level of p53. The two proteins are linked by a negative regulatory feedback loop and physically bind to each other via a putative helix formed by residues 18-26 of p53 TAD and its binding pocket located within the N-terminal 100 residue domain of mdm2 (Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J. and Pavletich, N. P. (1996) Science 274, 948-953). In a previous report, we have demonstrated that p53 TAD in the mdm2-freee state is mostly unstructured but contains two nascent turns in addition to a "preformed" helix that is the same as the putative helix mediating p53-mdm2 binding. Here, using heteronuclear multidimensional NMR methods, we show that the two nascent turn motifs in p53 TAD, turn I (residues 40-45) and turn II (residues 49-54), are also capable of binding to mdm2. In particular, the turn II motif has a higher mdm2-binding affinity (~20
J. Biol. Chem, 10.1074/jbc.M508578200
Submitted on August 4, 2005
Revised on September 9, 2005
Accepted on September 13, 2005
Structural details on MDM2-P53 interaction
M) than the turn I and targets the same site in mdm2 as the helix. Upon mdm2 binding this motif becomes a well-defined full helix turn whose hydrophobic face formed by the side chains of Ile50, Trp53, and Phe54 inserts deeply into the helix-binding pocket. Our results suggest that p53-mdm2 binding is subtler than previously thought and involves global contacts such as multiple "non-contiguous" minimally-structured motifs instead of being localized to one small helix mini-domain in p53 TAD.
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