Abstract
Cell signaling that culminates in posttranslational modifications directs protein activity. Here we report how multiple Ca2+-dependent phosphorylation sites within the transcription activator Ets-1 act additively to produce graded DNA binding affinity. Nuclear magnetic resonance spectroscopic analyses show that phosphorylation shifts Ets-1 from a dynamic conformation poised to bind DNA to a well-folded inhibited state. These phosphates lie in an unstructured flexible region that functions as the allosteric effector of autoinhibition. Variable phosphorylation thus serves as a "rheostat" for cell signaling to fine-tune transcription at the level of DNA binding.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Allosteric Regulation
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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DNA / metabolism*
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Hydrophobic and Hydrophilic Interactions
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Mice
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Nuclear Magnetic Resonance, Biomolecular
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Phosphorylation
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Protein Binding
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Protein Conformation
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Protein Folding
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-ets
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Signal Transduction
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Transcription Factors / chemistry*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Ets1 protein, mouse
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-ets
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Transcription Factors
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DNA
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases