Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions
Abstract Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we pre...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46236-5 |
| _version_ | 1797273871497297920 |
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| author | Rosa Antón Miguel Á. Treviño David Pantoja-Uceda Sara Félix María Babu Eurico J. Cabrita Markus Zweckstetter Philip Tinnefeld Andrés M. Vera Javier Oroz |
| author_facet | Rosa Antón Miguel Á. Treviño David Pantoja-Uceda Sara Félix María Babu Eurico J. Cabrita Markus Zweckstetter Philip Tinnefeld Andrés M. Vera Javier Oroz |
| author_sort | Rosa Antón |
| collection | DOAJ |
| description | Abstract Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome. |
| first_indexed | 2024-03-07T14:50:21Z |
| format | Article |
| id | doaj.art-3794aa1413964515962ab2aa2be23a71 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:50:21Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-3794aa1413964515962ab2aa2be23a712024-03-05T19:42:35ZengNature PortfolioNature Communications2041-17232024-03-0115111410.1038/s41467-024-46236-5Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansionsRosa Antón0Miguel Á. Treviño1David Pantoja-Uceda2Sara Félix3María Babu4Eurico J. Cabrita5Markus Zweckstetter6Philip Tinnefeld7Andrés M. Vera8Javier Oroz9Instituto de Química Física Blas Cabrera (IQF), CSICInstituto de Química Física Blas Cabrera (IQF), CSICInstituto de Química Física Blas Cabrera (IQF), CSICAssociate Laboratory i4HB – Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de LisboaGerman Center for Neurodegenerative Diseases (DZNE)Associate Laboratory i4HB – Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de LisboaGerman Center for Neurodegenerative Diseases (DZNE)Department of Chemistry and Center for NanoScience, Ludwig-Maximilians-Universität MünchenDepartment of Chemistry and Center for NanoScience, Ludwig-Maximilians-Universität MünchenInstituto de Química Física Blas Cabrera (IQF), CSICAbstract Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome.https://doi.org/10.1038/s41467-024-46236-5 |
| spellingShingle | Rosa Antón Miguel Á. Treviño David Pantoja-Uceda Sara Félix María Babu Eurico J. Cabrita Markus Zweckstetter Philip Tinnefeld Andrés M. Vera Javier Oroz Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions Nature Communications |
| title | Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions |
| title_full | Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions |
| title_fullStr | Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions |
| title_full_unstemmed | Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions |
| title_short | Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions |
| title_sort | alternative low populated conformations prompt phase transitions in polyalanine repeat expansions |
| url | https://doi.org/10.1038/s41467-024-46236-5 |
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