DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility
Summary: Transcription factors regulate gene expression by binding to DNA. They have disordered regions and specific DNA-binding domains. Binding to DNA causes structural changes, including folding and interactions with other molecules. The FoxP subfamily of transcription factors in humans is unique...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223013056 |
| _version_ | 1797774480390488064 |
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| author | Ricardo Coñuecar Isabel Asela Maira Rivera Pablo Galaz-Davison Jorge González-Higueras George L. Hamilton Felipe Engelberger César A. Ramírez-Sarmiento Jorge Babul Hugo Sanabria Exequiel Medina |
| author_facet | Ricardo Coñuecar Isabel Asela Maira Rivera Pablo Galaz-Davison Jorge González-Higueras George L. Hamilton Felipe Engelberger César A. Ramírez-Sarmiento Jorge Babul Hugo Sanabria Exequiel Medina |
| author_sort | Ricardo Coñuecar |
| collection | DOAJ |
| description | Summary: Transcription factors regulate gene expression by binding to DNA. They have disordered regions and specific DNA-binding domains. Binding to DNA causes structural changes, including folding and interactions with other molecules. The FoxP subfamily of transcription factors in humans is unique because they can form heterotypic interactions without DNA. However, it is unclear how they form heterodimers and how DNA binding affects their function. We used computational and experimental methods to study the structural changes in FoxP1’s DNA-binding domain when it forms a heterodimer with FoxP2. We found that FoxP1 has complex and diverse conformational dynamics, transitioning between compact and extended states. Surprisingly, DNA binding increases the flexibility of FoxP1, contrary to the typical folding-upon-binding mechanism. In addition, we observed a 3-fold increase in the rate of heterodimerization after FoxP1 binds to DNA. These findings emphasize the importance of structural flexibility in promoting heterodimerization to form transcriptional complexes. |
| first_indexed | 2024-03-12T22:21:43Z |
| format | Article |
| id | doaj.art-5778b6ad5bb047b986f85bd9562c7259 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-12T22:21:43Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-5778b6ad5bb047b986f85bd9562c72592023-07-23T04:56:00ZengElsevieriScience2589-00422023-07-01267107228DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibilityRicardo Coñuecar0Isabel Asela1Maira Rivera2Pablo Galaz-Davison3Jorge González-Higueras4George L. Hamilton5Felipe Engelberger6César A. Ramírez-Sarmiento7Jorge Babul8Hugo Sanabria9Exequiel Medina10Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, ChileDepartamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, ChileInstitute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile; ANID – Millennium Science Initiative Program – Millennium Institute for Integrative Biology (iBio), Santiago 8331150, ChileInstitute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile; ANID – Millennium Science Initiative Program – Millennium Institute for Integrative Biology (iBio), Santiago 8331150, ChileInstitute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile; ANID – Millennium Science Initiative Program – Millennium Institute for Integrative Biology (iBio), Santiago 8331150, ChileDepartment of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USAInstitute for Drug Discovery, Leipzig University Medical School, 04107 Leipzig, GermanyInstitute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile; ANID – Millennium Science Initiative Program – Millennium Institute for Integrative Biology (iBio), Santiago 8331150, ChileDepartamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile; Corresponding authorDepartment of Physics & Astronomy, Clemson University, Clemson, SC 29634, USA; Corresponding authorDepartamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile; Department of Physics & Astronomy, Clemson University, Clemson, SC 29634, USA; Corresponding authorSummary: Transcription factors regulate gene expression by binding to DNA. They have disordered regions and specific DNA-binding domains. Binding to DNA causes structural changes, including folding and interactions with other molecules. The FoxP subfamily of transcription factors in humans is unique because they can form heterotypic interactions without DNA. However, it is unclear how they form heterodimers and how DNA binding affects their function. We used computational and experimental methods to study the structural changes in FoxP1’s DNA-binding domain when it forms a heterodimer with FoxP2. We found that FoxP1 has complex and diverse conformational dynamics, transitioning between compact and extended states. Surprisingly, DNA binding increases the flexibility of FoxP1, contrary to the typical folding-upon-binding mechanism. In addition, we observed a 3-fold increase in the rate of heterodimerization after FoxP1 binds to DNA. These findings emphasize the importance of structural flexibility in promoting heterodimerization to form transcriptional complexes.http://www.sciencedirect.com/science/article/pii/S2589004223013056BiochemistryMolecular biologyStructural biology |
| spellingShingle | Ricardo Coñuecar Isabel Asela Maira Rivera Pablo Galaz-Davison Jorge González-Higueras George L. Hamilton Felipe Engelberger César A. Ramírez-Sarmiento Jorge Babul Hugo Sanabria Exequiel Medina DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility iScience Biochemistry Molecular biology Structural biology |
| title | DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility |
| title_full | DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility |
| title_fullStr | DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility |
| title_full_unstemmed | DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility |
| title_short | DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility |
| title_sort | dna facilitates heterodimerization between human transcription factors foxp1 and foxp2 by increasing their conformational flexibility |
| topic | Biochemistry Molecular biology Structural biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223013056 |
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