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Originally published In Press as doi:10.1074/jbc.M206327200 on September 6, 2002

J. Biol. Chem., Vol. 277, Issue 47, 45529-45536, November 22, 2002
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Structural Analysis of the Autoinhibition of Ets-1 and Its Role in Protein Partnerships*

Colin W. GarvieDagger , Miles A. Pufall§, Barbara J. Graves§, and Cynthia WolbergerDagger

From the Dagger  Department of Biophysics and Biophysical Chemistry and the Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185 and the § Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550

The DNA-binding activity of the eukaryotic transcription factor Ets-1 (E26 avian erythroblastosis virus oncogene-E twenty-six) is negatively regulated by inhibitory regions that flank the ETS domain. Based on the results of solution studies, these N- and C-terminal inhibitory regions have been proposed to pack against the ETS domain and form an autoinhibitory module whose N terminus partially unfolds upon binding of Ets-1 to DNA. Mutations that disrupt autoinhibition of DNA binding also cause a structural change in the inhibitory region. We report here a crystallographic study of fragments of Ets-1 that provide structural details of the inhibitory module and the structural transition that accompanies DNA binding. The structures of free and DNA-bound Ets-1 fragments containing the ETS domain and the inhibitory regions confirm that the N-terminal inhibitory region contains two alpha -helices one of which unfolds upon Ets-1 binding to DNA. The observations from the crystal structure, coupled with mutagenesis experiments, allow us to propose a model for the inhibited form of Ets-1 and lend insight into the flexible interaction between Ets-1 and the acute myeloid leukemia 1 protein, AML1 (RUNX1).

* This work was supported by the Howard Hughes Medical Institute (to C. W.), by the National Institutes of Health (Research Grant R01 GM38663 to B. J. G. and Fellowship Grants T32-CA93247 and T32-GM08537 to M. A. P.), and by the Huntsman Cancer Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code 1MD0 and 1MDM) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

To whom correspondence should be addressed: Dept. of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205-2185. Tel.: 410-955-0728; Fax: 410-614-8648; E-mail: cwolberg@jhmi.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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