Allosteric activation mechanism of DriD, a WYL-domain containing transcription regulator
Abstract WYL-domain containing transcription factors regulate fundamental processes in bacterial physiology, yet how these proteins sense cellular cues to elicit an allosteric response is not well understood. Here we describe the allosteric activation mechanism of DriD, a Caulobacter crescentus homo...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08111-x |
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| author | Emily Cannistraci Bindu Y. Srinivasu Jose Chavez Orozco Kevin Gozzi Thomas E. Wales Maria A. Schumacher |
| author_facet | Emily Cannistraci Bindu Y. Srinivasu Jose Chavez Orozco Kevin Gozzi Thomas E. Wales Maria A. Schumacher |
| author_sort | Emily Cannistraci |
| collection | DOAJ |
| description | Abstract WYL-domain containing transcription factors regulate fundamental processes in bacterial physiology, yet how these proteins sense cellular cues to elicit an allosteric response is not well understood. Here we describe the allosteric activation mechanism of DriD, a Caulobacter crescentus homodimeric WYL-domain containing transcription regulator that activates a non-canonical DNA damage pathway. DriD senses ssDNA, produced upon DNA damage via interaction with its WYL domain. This stimulates DriD target DNA binding. However, its DNA-binding domains (DNABDs) are 50 Å from the WYL-domains and linked by a three-helix bundle domain (3HB). Using a combination of crystallography, biochemistry, and HDX-MS we unveil an allosteric mechanism whereby an inhibitory interaction, formed between the DriD DNABD and 3HB in the apo form, is freed upon ssDNA binding, allowing target DNA binding. These findings may serve as a model for understanding activation by the large family of homodimeric WYL activators, including those in pathogenic bacteria. |
| format | Article |
| id | doaj-art-e0a747167de8443a8f9563dfa40617a2 |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-e0a747167de8443a8f9563dfa40617a22025-08-20T01:47:29ZengNature PortfolioCommunications Biology2399-36422025-04-018111510.1038/s42003-025-08111-xAllosteric activation mechanism of DriD, a WYL-domain containing transcription regulatorEmily Cannistraci0Bindu Y. Srinivasu1Jose Chavez Orozco2Kevin Gozzi3Thomas E. Wales4Maria A. Schumacher5Department of Biochemistry, 307 Research Dr., Box 3711, Duke University Medical CenterDepartment of Chemistry and Chemical Biology, Northeastern UniversityDepartment of Biochemistry, 307 Research Dr., Box 3711, Duke University Medical Center100 Edwin H Land Blvd, Harvard University CambridgeDepartment of Chemistry and Chemical Biology, Northeastern UniversityDepartment of Biochemistry, 307 Research Dr., Box 3711, Duke University Medical CenterAbstract WYL-domain containing transcription factors regulate fundamental processes in bacterial physiology, yet how these proteins sense cellular cues to elicit an allosteric response is not well understood. Here we describe the allosteric activation mechanism of DriD, a Caulobacter crescentus homodimeric WYL-domain containing transcription regulator that activates a non-canonical DNA damage pathway. DriD senses ssDNA, produced upon DNA damage via interaction with its WYL domain. This stimulates DriD target DNA binding. However, its DNA-binding domains (DNABDs) are 50 Å from the WYL-domains and linked by a three-helix bundle domain (3HB). Using a combination of crystallography, biochemistry, and HDX-MS we unveil an allosteric mechanism whereby an inhibitory interaction, formed between the DriD DNABD and 3HB in the apo form, is freed upon ssDNA binding, allowing target DNA binding. These findings may serve as a model for understanding activation by the large family of homodimeric WYL activators, including those in pathogenic bacteria.https://doi.org/10.1038/s42003-025-08111-x |
| spellingShingle | Emily Cannistraci Bindu Y. Srinivasu Jose Chavez Orozco Kevin Gozzi Thomas E. Wales Maria A. Schumacher Allosteric activation mechanism of DriD, a WYL-domain containing transcription regulator Communications Biology |
| title | Allosteric activation mechanism of DriD, a WYL-domain containing transcription regulator |
| title_full | Allosteric activation mechanism of DriD, a WYL-domain containing transcription regulator |
| title_fullStr | Allosteric activation mechanism of DriD, a WYL-domain containing transcription regulator |
| title_full_unstemmed | Allosteric activation mechanism of DriD, a WYL-domain containing transcription regulator |
| title_short | Allosteric activation mechanism of DriD, a WYL-domain containing transcription regulator |
| title_sort | allosteric activation mechanism of drid a wyl domain containing transcription regulator |
| url | https://doi.org/10.1038/s42003-025-08111-x |
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