8PUI

human PHOX2B C-terminal domain including the polyA fragment at 298K

8PUI の概要

• エントリーDOI: 10.2210/pdb8pui/pdb
• 関連するPDBエントリー: 8P80
• NMR情報: BMRB: 51979
• 分子名称: Paired mesoderm homeobox protein 2B (1 entity in total)
• 機能のキーワード: cchs, polya, homorepeat, trinucleotide repeat expansion, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 7535.39

構造登録者

Anton, R.,Trevino, M.A.,Pantoja-Uceda, D.,Felix, S.,Babu, M.,Cabrita, E.J.,Zweckstetter, M.,Tinnefeld, P.,Vera, A.M.,Oroz, J. (登録日: 2023-07-17, 公開日: 2024-03-13)

主引用文献

Anton, R.,Trevino, M.A.,Pantoja-Uceda, D.,Felix, S.,Babu, M.,Cabrita, E.J.,Zweckstetter, M.,Tinnefeld, P.,Vera, A.M.,Oroz, J.
Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions.
Nat Commun, 15:1925-1925, 2024

PubMed 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.

PubMed: 38431667
DOI: 10.1038/s41467-024-46236-5

実験手法

SOLUTION NMR