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Variable Control of Ets-1 DNA Binding by Multiple Phosphates in an Unstructured Region
Miles A. Pufall,1Gregory M. Lee,2Mary L. Nelson,1Hyun-Seo Kang,2Algirdas Velyvis,3Lewis E. Kay,3Lawrence P. McIntosh,2Barbara J. Graves1*
Cell signaling that culminates in posttranslational modificationsdirects protein activity. Here we report how multiple Ca2+-dependentphosphorylation sites within the transcription activator Ets-1act additively to produce graded DNA binding affinity. Nuclearmagnetic resonance spectroscopic analyses show that phosphorylationshifts Ets-1 from a dynamic conformation poised to bind DNAto a well-folded inhibited state. These phosphates lie in anunstructured flexible region that functions as the allostericeffector of autoinhibition. Variable phosphorylation thus servesas a "rheostat" for cell signaling to fine-tune transcriptionat the level of DNA binding.
1 Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112–5550, USA. 2 Department of Biochemistry and Molecular Biology, Department of Chemistry, and The Michael Smith Laboratory, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada. 3 Departments of Medical Genetics, Biochemistry, and Chemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
* To whom correspondence should be addressed. E-mail: Barbara.Graves{at}hci.utah.edu
Phosphorylation by PKA potentiates retinoic acid receptor {alpha} activity by means of increasing interaction with and phosphorylation by cyclin H/cdk7.
E. Gaillard, N. Bruck, Y. Brelivet, G. Bour, S. Lalevee, A. Bauer, O. Poch, D. Moras, and C. Rochette-Egly (2006)
PNAS
103, 9548-9553
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Cooperative DNA Binding with AP-1 Proteins Is Required for Transformation by EWS-Ets Fusion Proteins..
