Home > Publications Database > Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions. > print

001     268494
005     20240403103733.0
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024 7 _ |a 10.1038/s41467-024-46236-5
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041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Antón, Rosa
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245 _ _ |a Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions.
260 _ _ |a [London]
|c 2024
|b Nature Publishing Group UK
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520 _ _ |a 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.
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650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Homeodomain Proteins: metabolism
|2 MeSH
650 _ 2 |a Transcription Factors: metabolism
|2 MeSH
650 _ 2 |a Peptides: genetics
|2 MeSH
650 _ 2 |a Peptides: chemistry
|2 MeSH
650 _ 2 |a Hypoventilation: genetics
|2 MeSH
650 _ 2 |a Hypoventilation: congenital
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Mammals: metabolism
|2 MeSH
650 _ 7 |a Homeodomain Proteins
|2 NLM Chemicals
650 _ 7 |a polyalanine
|0 25191-17-7
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650 _ 7 |a Transcription Factors
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650 _ 7 |a Peptides
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700 1 _ |a Treviño, Miguel Á
|0 0000-0002-0738-5973
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700 1 _ |a Pantoja-Uceda, David
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700 1 _ |a Félix, Sara
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700 1 _ |a Babu, Maria
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700 1 _ |a Cabrita, Eurico J
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700 1 _ |a Zweckstetter, Markus
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700 1 _ |a Tinnefeld, Philip
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700 1 _ |a Vera, Andrés M
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700 1 _ |a Oroz, Javier
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773 _ _ |a 10.1038/s41467-024-46236-5
|g Vol. 15, no. 1, p. 1925
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|t Nature Communications
|v 15
|y 2024
|x 2041-1723
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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