ArticleProceedings of the National Academy of Sciences of the United States of America2016
Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 37 citations in OpenAlex.
- Evolutionary causes and consequences of gene duplication.Nature reviews. Genetics · 2026Review
- Marine-Derived Steroids for Cancer Treatment: Search for Potential Selective Glucocorticoid Receptor Agonists/Modulators (SEGRAMs).Marine drugs · 2025Review
- Molecular model of TFIIH recruitment to the transcription-coupled repair machinery.Nature communications · 2025Article
- Molecular architecture and functional dynamics of the pre-incision complex in nucleotide excision repair.Nature communications · 2024Article
- Decoding the dual recognition mechanism of the glucocorticoid receptor for DNA and RNA: sequence versus shape.Scientific reports · 2023Article
- Review
- Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication.Nature structural & molecular biology · 2023Article
- Mechanisms of protein evolution.Protein science : a publication of the Protein Society · 2022Review
- Co-evolution of interacting proteins through non-contacting and non-specific mutations.Nature ecology & evolution · 2022Article
- Structural insights into glucocorticoid receptor function.Biochemical Society transactions · 2021Review
- One evolutionarily selected amino acid variation is sufficient to provide functional specificity in the cold shock protein paralogs of Staphylococcus aureus.Molecular microbiology · 2020Article
- Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism.Frontiers in endocrinology · 2020Review
- GR Dimerization and the Impact of GR Dimerization on GR Protein Stability and Half-Life.Frontiers in immunology · 2019Review
- Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements.Nature communications · 2018Article
- Conservation of Specificity in Two Low-Specificity Proteins.Biochemistry · 2018Article
- Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes.Nucleic acids research · 2017Article
- Glucocorticoid receptor control of transcription: precision and plasticity via allostery.Nature reviews. Molecular cell biology · 2017Review
- Cognition, Information Fields and Hologenomic Entanglement: Evolution in Light and Shadow.Biology · 2016Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
Abstract
Many genomes contain families of paralogs--proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and negative glucocorticoid response elements (nGREs). We show that binding to nGREs is a property of the glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other members of the steroid receptor family. Using phylogenetic, structural, biochemical, and molecular dynamics techniques, we show that the ancestral DBD from which GR and its paralogs evolved was capable of binding both nGRE and (+)GRE sequences because of the ancestral DBD's ability to assume multiple DNA-bound conformations. Subsequent amino acid substitutions in duplicated daughter genes selectively restricted protein conformational space, causing this dual DNA-binding specificity to be selectively enhanced in the GR lineage and lost in all others. Key substitutions that determined the receptors' response element-binding specificity were far from the proteins' DNA-binding interface and interacted epistatically to change the DBD's function through DNA-induced allosteric mechanisms. These amino acid substitutions subdivided both the conformational and functional space of the ancestral DBD among the present-day receptors, allowing a paralogous family of transcription factors to control disparate transcriptional programs despite high sequence identity.
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