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@ARTICLE{Antn:268494,
      author       = {Antón, Rosa and Treviño, Miguel Á and Pantoja-Uceda,
                      David and Félix, Sara and Babu, Maria and Cabrita, Eurico J
                      and Zweckstetter, Markus and Tinnefeld, Philip and Vera,
                      Andrés M and Oroz, Javier},
      title        = {{A}lternative low-populated conformations prompt phase
                      transitions in polyalanine repeat expansions.},
      journal      = {Nature Communications},
      volume       = {15},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DZNE-2024-00240},
      pages        = {1925},
      year         = {2024},
      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.},
      keywords     = {Animals / Humans / Homeodomain Proteins: metabolism /
                      Transcription Factors: metabolism / Peptides: genetics /
                      Peptides: chemistry / Hypoventilation: genetics /
                      Hypoventilation: congenital / Mutation / Mammals: metabolism
                      / Homeodomain Proteins (NLM Chemicals) / polyalanine (NLM
                      Chemicals) / Transcription Factors (NLM Chemicals) /
                      Peptides (NLM Chemicals)},
      cin          = {AG Zweckstetter},
      ddc          = {500},
      cid          = {I:(DE-2719)1410001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC10908835},
      pubmed       = {pmid:38431667},
      doi          = {10.1038/s41467-024-46236-5},
      url          = {https://pub.dzne.de/record/268494},
}