Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha
The neuronal DNA-/RNA-binding protein Pur-alpha is a transcription regulator and core factor for mRNA localization. Pur-alpha-deficient mice die after birth with pleiotropic neuronal defects. Here, we report the crystal structure of the DNA-/RNA-binding domain of Pur-alpha in complex with ssDNA. It...
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| Format: | Article |
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eLife Sciences Publications Ltd
2016-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/11297 |
| _version_ | 1797997663226953728 |
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| author | Janine Weber Han Bao Christoph Hartlmüller Zhiqin Wang Almut Windhager Robert Janowski Tobias Madl Peng Jin Dierk Niessing |
| author_facet | Janine Weber Han Bao Christoph Hartlmüller Zhiqin Wang Almut Windhager Robert Janowski Tobias Madl Peng Jin Dierk Niessing |
| author_sort | Janine Weber |
| collection | DOAJ |
| description | The neuronal DNA-/RNA-binding protein Pur-alpha is a transcription regulator and core factor for mRNA localization. Pur-alpha-deficient mice die after birth with pleiotropic neuronal defects. Here, we report the crystal structure of the DNA-/RNA-binding domain of Pur-alpha in complex with ssDNA. It reveals base-specific recognition and offers a molecular explanation for the effect of point mutations in the 5q31.3 microdeletion syndrome. Consistent with the crystal structure, biochemical and NMR data indicate that Pur-alpha binds DNA and RNA in the same way, suggesting binding modes for tri- and hexanucleotide-repeat RNAs in two neurodegenerative RNAopathies. Additionally, structure-based in vitro experiments resolved the molecular mechanism of Pur-alpha's unwindase activity. Complementing in vivo analyses in Drosophila demonstrated the importance of a highly conserved phenylalanine for Pur-alpha's unwinding and neuroprotective function. By uncovering the molecular mechanisms of nucleic-acid binding, this study contributes to understanding the cellular role of Pur-alpha and its implications in neurodegenerative diseases. |
| first_indexed | 2024-04-11T10:35:12Z |
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| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:35:12Z |
| publishDate | 2016-01-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj.art-efda59bbda284b3ba79078c5ac5326db2022-12-22T04:29:18ZengeLife Sciences Publications LtdeLife2050-084X2016-01-01510.7554/eLife.11297Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alphaJanine Weber0Han Bao1Christoph Hartlmüller2Zhiqin Wang3Almut Windhager4Robert Janowski5Tobias Madl6Peng Jin7Dierk Niessing8https://orcid.org/0000-0002-5589-369XInstitute of Structural Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, GermanyDepartment of Human Genetics, Emory University, Atlanta, United StatesCenter for Integrated Protein Science Munich, Department of Chemistry, Technische Universität München, Munich, GermanyDepartment of Human Genetics, Emory University, Atlanta, United StatesInstitute of Structural Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Structural Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, GermanyInstitute of Structural Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Center for Integrated Protein Science Munich, Department of Chemistry, Technische Universität München, Munich, Germany; Institute of Molecular Biology & Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria; Omics Center Graz, BioTechMed Graz, Graz, AustriaDepartment of Human Genetics, Emory University, Atlanta, United StatesInstitute of Structural Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department Cell Biology, Biomedical Center of the Ludwig-Maximilians-University München, Planegg-Martinsried, GermanyThe neuronal DNA-/RNA-binding protein Pur-alpha is a transcription regulator and core factor for mRNA localization. Pur-alpha-deficient mice die after birth with pleiotropic neuronal defects. Here, we report the crystal structure of the DNA-/RNA-binding domain of Pur-alpha in complex with ssDNA. It reveals base-specific recognition and offers a molecular explanation for the effect of point mutations in the 5q31.3 microdeletion syndrome. Consistent with the crystal structure, biochemical and NMR data indicate that Pur-alpha binds DNA and RNA in the same way, suggesting binding modes for tri- and hexanucleotide-repeat RNAs in two neurodegenerative RNAopathies. Additionally, structure-based in vitro experiments resolved the molecular mechanism of Pur-alpha's unwindase activity. Complementing in vivo analyses in Drosophila demonstrated the importance of a highly conserved phenylalanine for Pur-alpha's unwinding and neuroprotective function. By uncovering the molecular mechanisms of nucleic-acid binding, this study contributes to understanding the cellular role of Pur-alpha and its implications in neurodegenerative diseases.https://elifesciences.org/articles/11297DNA-/RNA-protein interactionDNA unwindingFXTASALS5q31.3 microdeletion syndromeX-ray crystallography |
| spellingShingle | Janine Weber Han Bao Christoph Hartlmüller Zhiqin Wang Almut Windhager Robert Janowski Tobias Madl Peng Jin Dierk Niessing Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha eLife DNA-/RNA-protein interaction DNA unwinding FXTAS ALS 5q31.3 microdeletion syndrome X-ray crystallography |
| title | Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha |
| title_full | Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha |
| title_fullStr | Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha |
| title_full_unstemmed | Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha |
| title_short | Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha |
| title_sort | structural basis of nucleic acid recognition and double strand unwinding by the essential neuronal protein pur alpha |
| topic | DNA-/RNA-protein interaction DNA unwinding FXTAS ALS 5q31.3 microdeletion syndrome X-ray crystallography |
| url | https://elifesciences.org/articles/11297 |
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