ArticleProtein science : a publication of the Protein Society1999
Mutants of ETS domain PU.1 and GGAA/T recognition: free energies and kinetics.
Article in Protein science : a publication of the Protein Society, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 22 citations in OpenAlex.
- DNA selection by the master transcription factor PU.1.Cell reports · 2023Article
- Mapping interfacial hydration in ETS-family transcription factor complexes with DNA: a chimeric approach.Nucleic acids research · 2018Article
- RAG1 targeting in the genome is dominated by chromatin interactions mediated by the non-core regions of RAG1 and RAG2.Nucleic acids research · 2016Article
- IL-32θ inhibits monocytic differentiation of leukemia cells by attenuating expression of transcription factor PU.1.Oncotarget · 2015Article
- Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell.BMC systems biology · 2014Article
- Probing the electrostatics and pharmacological modulation of sequence-specific binding by the DNA-binding domain of the ETS family transcription factor PU.1: a binding affinity and kinetics investigation.Journal of molecular biology · 2013Article
- Sequence discrimination by DNA-binding domain of ETS family transcription factor PU.1 is linked to specific hydration of protein-DNA interface.The Journal of biological chemistry · 2012Article
- Genomic and biochemical insights into the specificity of ETS transcription factors.Annual review of biochemistry · 2011Review
- Transition state for protein-DNA recognition.Proceedings of the National Academy of Sciences of the United States of America · 2008Article
- Energetics of the protein-DNA-water interaction.BMC structural biology · 2007Article
- Identification of a PU.1-IRF4 protein interaction surface predicted by chemical exchange line broadening.Proceedings of the National Academy of Sciences of the United States of America · 2003Article
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4 authors at 3 institutions in 1 country.
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Abstract
The ETS family members display specific DNA binding site preferences. As an example, PU.1 and ETS-1 recognize different DNA sequences with a core element centered over 5'-GGAA-3' and 5'-GGAA/T-3', respectively. To understand the molecular basis of this recognition, we carried out site-directed mutagenesis experiments followed by DNA binding studies that use electrophoretic mobility shift assay (EMSA) and surface plasmon resonance methods. EMSA experiments identified amino acid changes A231S and/or N236Y as being important for PU.1 recognition of both 5'-GGAA-3' and 5'-GGAT-3' containing oligonucleotides. To confirm these data and obtain accurate binding parameters, we performed kinetic studies using surface plasmon resonance on these mutants. The N236Y substitution revealed a weak protein-DNA interaction with the 5'-GGAA-3' containing oligonucleotide caused by a faster release of the protein from the DNA (k(off) tenfold higher than the wild-type protein). With the double mutant A231S-N236Y, we obtained an increase in binding affinity and stability toward both 5'-GGAA-3' and 5'-GGAT-3' containing oligonucleotides. We propose that substitution of alanine for serine introduces an oxygen atom that can accept hydrogen and interact with potential water molecules or other atoms to make an energetically favorable hydrogen bond with both 5'-GGAA-3' and 5'-GGAT-3' oligonucleotides. The free energy of dissociation for the double mutant A231S-N236Y with 5'-GGAA-3' (delta deltaG((A231S-N236Y) - (N236Y)) = -1.2 kcal mol confirm the stabilizing effect of this mutant in the protein-DNA complex formation. We conclude that N236Y mutation relaxes the specificity toward 5'-GGAA-3' and 5'-GGAT-3' sequences, while A231S mutation modulates the degree of specificity toward 5'-GGAA-3' and 5'GGAT-3' sequences. This study explains why wild-type PU.1 does not recognize 5'-GGAT-3' sequences and in addition broadens our understanding of 5'-GGAA/T-3' recognition by ETS protein family members.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.