TY  - JOUR
AU  - Antón, Rosa
AU  - Treviño, Miguel Á
AU  - Pantoja-Uceda, David
AU  - Félix, Sara
AU  - Babu, Maria
AU  - Cabrita, Eurico J
AU  - Zweckstetter, Markus
AU  - Tinnefeld, Philip
AU  - Vera, Andrés M
AU  - Oroz, Javier
TI  - Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2024-00240
SP  - 1925
PY  - 2024
AB  - 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.
KW  - Animals
KW  - Humans
KW  - Homeodomain Proteins: metabolism
KW  - Transcription Factors: metabolism
KW  - Peptides: genetics
KW  - Peptides: chemistry
KW  - Hypoventilation: genetics
KW  - Hypoventilation: congenital
KW  - Mutation
KW  - Mammals: metabolism
KW  - Homeodomain Proteins (NLM Chemicals)
KW  - polyalanine (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - Peptides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10908835
C6  - pmid:38431667
DO  - DOI:10.1038/s41467-024-46236-5
UR  - https://pub.dzne.de/record/268494
ER  -