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1.
Int J Mol Sci ; 25(18)2024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39337404

RESUMEN

The pathological process of prion diseases implicates that the normal physiological cellular prion protein (PrPC) converts into misfolded abnormal scrapie prion (PrPSc) through post-translational modifications that increase ß-sheet conformation. We recently demonstrated that HuPrP(90-231) thermal unfolding is partially irreversible and characterized by an intermediate state (ß-PrPI), which has been revealed to be involved in the initial stages of PrPC fibrillation, with a seeding activity comparable to that of human infectious prions. In this study, we report the thermal unfolding characterization, in cell-mimicking conditions, of the truncated (HuPrP(90-231)) and full-length (HuPrP(23-231)) human prion protein by means of CD and NMR spectroscopy, revealing that HuPrP(90-231) thermal unfolding is characterized by two successive transitions, as in buffer solution. The amyloidogenic propensity of HuPrP(90-231) under crowded conditions has also been investigated. Our findings show that although the prion intermediate, structurally very similar to ß-PrPI, forms at a lower temperature compared to when it is dissolved in buffer solution, in cell-mimicking conditions, the formation of prion fibrils requires a longer incubation time, outlining how molecular crowding influences both the equilibrium states of PrP and its kinetic pathways of folding and aggregation.


Asunto(s)
Proteínas Priónicas , Desplegamiento Proteico , Humanos , Proteínas Priónicas/química , Proteínas Priónicas/metabolismo , Amiloide/química , Amiloide/metabolismo , Pliegue de Proteína , Temperatura
2.
Chem Sci ; 15(23): 8858-8872, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38873078

RESUMEN

An expansion of poly-alanine up to +13 residues in the C-terminus of the transcription factor PHOX2B underlies the onset of congenital central hypoventilation syndrome (CCHS). Recent studies demonstrated that the alanine tract expansion influences PHOX2B folding and activity. Therefore, structural information on PHOX2B is an important target for obtaining clues to elucidate the insurgence of the alanine expansion-related syndrome and also for defining a viable therapy. Here we report by NMR spectroscopy the structural characterization of the homeodomain (HD) of PHOX2B and HD + C-terminus PHOX2B protein, free and in the presence of the target DNA. The obtained structural data are then exploited to obtain a structural model of the PHOX2B-DNA interaction. In addition, the variant +7Ala, responsible for one of the most frequent forms of the syndrome, was analysed, showing different conformational proprieties in solution and a strong propensity to aggregation. Our data suggest that the elongated poly-alanine tract would be related to disease onset through a loss-of-function mechanism. Overall, this study paves the way for the future rational design of therapeutic drugs, suggesting as a possible therapeutic route the use of specific anti-aggregating molecules capable of preventing variant aggregation and possibly restoring the DNA-binding activity of PHOX2B.

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