HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 46, 38795-38802, November 18, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/46/38795    most recent M508578200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chi, S.-W. Articles by Han, K.-H. Search for Related Content PubMed PubMed Citation Articles by Chi, S.-W. Articles by Han, K.-H. Social Bookmarking                      What's this?

Structural Details on mdm2-p53 Interaction^*

Seung-Wook Chi, Si-Hyung Lee, Do-Hyoung Kim, Min-Jung Ahn, Jae-Sung Kim, Jin-Young Woo, Takuya Torizawa, Masatsune Kainosho, and Kyou-Hoon Han1

From the Protein Analysis and Design Laboratory, Division of Drug Discovery, Korea Research Institute of Bioscience and Biotechnology, Yusong P. O. Box 115, Daejon 305-600, Korea and CREST/JST and Graduate School of Science, Tokyo Metropolitan University, Minami-Ohsawa, Hachioji, Tokyo 192-0397, Japan

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 transactivation domain (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 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 µM) 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 Ile-50, Trp-53, and Phe-54 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.

Received for publication, August 4, 2005 , and in revised form, September 9, 2005.

^* This work has been supported by the KRIBB Research Initiative Pioneer Program (to K.-H. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 82-42-860-4250; Fax: 82-42-860-4259; E-mail: khhan600{at}kribb.re.kr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. S. Libich and G. Harauz Backbone Dynamics of the 18.5 kDa Isoform of Myelin Basic Protein Reveals Transient {alpha}-Helices and a Calmodulin-Binding Site Biophys. J., June 15, 2008; 94(12): 4847 - 4866. [Abstract] [Full Text] [PDF]

				Z. Chen, E. Knutson, S. Wang, L. A. Martinez, and T. Albrecht Stabilization of p53 in Human Cytomegalovirus-initiated Cells Is Associated with Sequestration of HDM2 and Decreased p53 Ubiquitination J. Biol. Chem., October 5, 2007; 282(40): 29284 - 29295. [Abstract] [Full Text] [PDF]

				S.-W. Chi, D.-H. Kim, S.-H. Lee, I. Chang, and K.-H. Han Pre-structured motifs in the natively unstructured preS1 surface antigen of hepatitis B virus Protein Sci., October 1, 2007; 16(10): 2108 - 2117. [Abstract] [Full Text] [PDF]

				D. P. Teufel, S. M. Freund, M. Bycroft, and A. R. Fersht Four domains of p300 each bind tightly to a sequence spanning both transactivation subdomains of p53 PNAS, April 24, 2007; 104(17): 7009 - 7014. [Abstract] [Full Text] [PDF]