Polyalanine expansions in PHOX2B cause protein loss of function in Ondine's Syndrome. Antón et al. show how.

Abnormal trinucleotide repeat expansion alter protein conformation causing malfunction and are associated with different human diseases. However, the role of these homorepeats is still unknown and scarce structural information is available. The transcription factor PHOX2B contains a polyalanine tract in its C-terminal region whose extension is related with an ultra-rare disease, the Congenital Central Hypoventilation Syndrome. In collaboration with scientist from DZNE/Max Planck Göttingen, U. Munich and U. Lisboa, researchers from the Blas Cabrera Institute have described the first structure of a homorepeat protein. In particular, they have observed that the polyalanine tract in PHOX2B adopts an alpha helical structure and that, unexpectedly, the polyalanine expansion in this protein promote new nascent conformations that prompt length-dependent phase transitions into solid biomolecular condensates that capture wild-type PHOX2B. Moreover, they have found that HSP70 and HSP90 chaperones are able to bind these new alternative structures impairing phase transitions. The data included in Antón et al. show for the first time the direct observation of nascent polymorphs in expanded proteins as PHOX2B, proposing unbalanced phase separation as a new pathophysiological mechanism in homorepeats expansion diseases. Antón R, Treviño MÁ, Pantoja-Uceda D, Félix S, Babu M, Cabrita EJ, Zweckstetter M, Tinnefeld P, Vera AM, Oroz J. Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions. Nat Commun. 2024 Mar 2;15(1):1925. doi: 10.1038/s41467-024-46236-5. PMID: 38431667.