Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions

Rosa Antón, Miguel Á. Treviño, David Pantoja-Uceda, Sara Félix, María Babu, Eurico J. Cabrita, Markus Zweckstetter, Philip Tinnefeld, Andrés M. Vera and Javier Oroz ()
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Rosa Antón: Instituto de Química Física Blas Cabrera (IQF), CSIC
Miguel Á. Treviño: Instituto de Química Física Blas Cabrera (IQF), CSIC
David Pantoja-Uceda: Instituto de Química Física Blas Cabrera (IQF), CSIC
Sara Félix: Universidade NOVA de Lisboa
María Babu: German Center for Neurodegenerative Diseases (DZNE)
Eurico J. Cabrita: Universidade NOVA de Lisboa
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)
Philip Tinnefeld: Ludwig-Maximilians-Universität München
Andrés M. Vera: Ludwig-Maximilians-Universität München
Javier Oroz: Instituto de Química Física Blas Cabrera (IQF), CSIC

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46236-5

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