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000268494 1001_ $$aAntón, Rosa$$b0
000268494 245__ $$aAlternative low-populated conformations prompt phase transitions in polyalanine repeat expansions.
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000268494 520__ $$aAbnormal 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.
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000268494 650_2 $$2MeSH$$aAnimals
000268494 650_2 $$2MeSH$$aHumans
000268494 650_2 $$2MeSH$$aHomeodomain Proteins: metabolism
000268494 650_2 $$2MeSH$$aTranscription Factors: metabolism
000268494 650_2 $$2MeSH$$aPeptides: genetics
000268494 650_2 $$2MeSH$$aPeptides: chemistry
000268494 650_2 $$2MeSH$$aHypoventilation: genetics
000268494 650_2 $$2MeSH$$aHypoventilation: congenital
000268494 650_2 $$2MeSH$$aMutation
000268494 650_2 $$2MeSH$$aMammals: metabolism
000268494 650_7 $$2NLM Chemicals$$aHomeodomain Proteins
000268494 650_7 $$025191-17-7$$2NLM Chemicals$$apolyalanine
000268494 650_7 $$2NLM Chemicals$$aTranscription Factors
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000268494 7001_ $$00000-0002-0738-5973$$aTreviño, Miguel Á$$b1
000268494 7001_ $$aPantoja-Uceda, David$$b2
000268494 7001_ $$00000-0003-2052-9828$$aFélix, Sara$$b3
000268494 7001_ $$0P:(DE-2719)2812749$$aBabu, Maria$$b4$$udzne
000268494 7001_ $$00000-0002-0720-2751$$aCabrita, Eurico J$$b5
000268494 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b6
000268494 7001_ $$aTinnefeld, Philip$$b7
000268494 7001_ $$00000-0002-3932-8236$$aVera, Andrés M$$b8
000268494 7001_ $$0P:(DE-2719)2810826$$aOroz, Javier$$b9
000268494 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-024-46236-5$$gVol. 15, no. 1, p. 1925$$n1$$p1925$$tNature Communications$$v15$$x2041-1723$$y2024
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