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

doi:10.1074/jbc.M206327200

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

Journal article

Open access

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

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

The Journal of biological chemistry, Vol.277(47), pp.45529-45536

11/22/2002

DOI: 10.1074/jbc.M206327200

PMID: 12221090

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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 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).

Protein Structure, Tertiary

Proto-Oncogene Proteins - metabolism

Peptide Fragments - metabolism

Mutagenesis, Site-Directed

Transcription Factors - chemistry

Protein Structure, Secondary

Models, Molecular

Crystallography, X-Ray

Proto-Oncogene Proteins - genetics

Proto-Oncogene Proteins - chemistry

Transcription Factors - genetics

Transcription Factors - metabolism

Peptide Fragments - chemistry

Protein Binding

Transcription, Genetic

Proto-Oncogene Protein c-ets-1

Nucleic Acid Conformation

Binding Sites

Proto-Oncogene Proteins c-ets

Details

Title: Subtitle: Structural analysis of the autoinhibition of Ets-1 and its role in protein partnerships
Creators: Colin W Garvie - Department of Biophysics and Biophysical Chemistry and the Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185, USA
Miles A Pufall
Barbara J Graves
Cynthia Wolberger
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.277(47), pp.45529-45536
DOI: 10.1074/jbc.M206327200
PMID: 12221090
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: R01 GM38663 / NIGMS NIH HHS T32-GM08537 / NIGMS NIH HHS R01 GM038663 / NIGMS NIH HHS T32-CA93247 / NCI NIH HHS
Language: English
Date published: 11/22/2002
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9984025255202771

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