Structural analysis of the autoinhibition of Ets-1 and its role in protein partnerships

Colin W. Garvie, Miles A. Pufall, Barbara J. Graves, Cynthia Wolberger

Research output: Contribution to journalArticlepeer-review

Abstract

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 α-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).

Original languageEnglish (US)
Pages (from-to)45529-45536
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number47
DOIs
StatePublished - Nov 22 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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