Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions
Rosa Antón1, Miguel Á Treviño1, David Pantoja-Uceda1
1Instituto de Química Física Blas Cabrera (IQF), CSIC, E-28006, Madrid, Spain.
Nature Communications
|March 2, 2024
Summary
Abnormal protein structures from repeat expansions cause incurable diseases. This study reveals how PHOX2B expansions trigger phase transitions, offering new therapeutic targets for congenital central hypoventilation syndrome.
Area of Science:
- Molecular Biology
- Structural Biology
- Genetics
Background:
- Trinucleotide repeat expansions cause incurable diseases by altering protein structure and function.
- Limited structural data on homorepeat expansions impedes therapeutic development.
Purpose of the Study:
- To elucidate the dynamic structure of the human PHOX2B C-terminal fragment, focusing on its polyalanine tract.
- To investigate the impact of polyalanine expansions on PHOX2B conformation and condensate formation.
Main Methods:
- Dynamic structural analysis of the PHOX2B C-terminal fragment.
- Investigation of polyalanine tract behavior under expansion.
- Observation of phase transition dynamics and chaperone interactions.
Main Results:
- Polyalanine expansions in PHOX2B extend the major α-helical conformation.
- Expanded PHOX2B undergoes length-dependent phase transitions into solid condensates.
- HSP70 and HSP90 chaperones bind to alternative PHOX2B conformations, inhibiting phase transitions.
Conclusions:
- Unbalanced phase transitions in expanded PHOX2B represent a distinct pathophysiological mechanism in homorepeat expansion diseases.
- Targeting biomolecular condensate modulation offers a therapeutic strategy for congenital central hypoventilation syndrome.
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