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Slow Misfolding of a Molten Globule form of a Mutant Prion Protein Variant into a β-rich Dimer

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dc.contributor.author PAL, SUMAN en_US
dc.contributor.author UDGAONKAR, JAYANT B. en_US
dc.date.accessioned 2024-09-06T10:42:10Z
dc.date.available 2024-09-06T10:42:10Z
dc.date.issued 2024-10 en_US
dc.identifier.citation Journal of Molecular Biology, 436(09), 168736. en_US
dc.identifier.issn 0022-2836 en_US
dc.identifier.issn 1089-8638 en_US
dc.identifier.uri https://doi.org/10.1016/j.jmb.2024.168736 en_US
dc.identifier.uri http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/9071
dc.description.abstract Misfolding of the prion protein is linked to multiple neurodegenerative diseases. A better understanding of the process requires the identification and structural characterization of intermediate conformations via which misfolding proceeds. In this study, three conserved aromatic residues (Tyr168, Phe174, and Tyr217) located in the C-terminal domain of mouse PrP (wt moPrP) were mutated to Ala. The resultant mutant protein, 3A moPrP, is shown to adopt a molten globule (MG)-like native conformation. Hydrogen-deuterium exchange studies coupled with mass spectrometry revealed that for 3A moPrP, the free energy gap between the MG-like native conformation and misfolding-prone partially unfolded forms is reduced. Consequently, 3A moPrP misfolds in native conditions even in the absence of salt, unlike wt moPrP, which requires the addition of salt to misfold. 3A moPrP misfolds to a β-rich dimer in the absence of salt, which can rapidly form an oligomer upon the addition of salt. In the presence of salt, 3A moPrP misfolds to a β-rich oligomer about a thousand-fold faster than wt moPrP. Importantly, the misfolded structure of the dimer is similar to that of the salt-induced oligomer. Misfolding to oligomer seems to be induced at the level of the dimeric unit by monomer–monomer association, and the oligomer grows by accretion of misfolded dimeric units. Additionally, it is shown that the conserved aromatic residues collectively stabilize not only monomeric protein, but also the structural core of the β-rich oligomers. Finally, it is also shown that 3A moPrP misfolds much faster to amyloid-fibrils than does the wt protein. en_US
dc.language.iso en en_US
dc.publisher Elsevier B.V. en_US
dc.subject Prion misfolding en_US
dc.subject Prion diseases en_US
dc.subject Mouse prion protein en_US
dc.subject Molten globule form en_US
dc.subject Aromatic residues en_US
dc.subject 2024 en_US
dc.subject 2024-SEP-WEEK1 en_US
dc.subject TOC-SEP-2024 en_US
dc.title Slow Misfolding of a Molten Globule form of a Mutant Prion Protein Variant into a β-rich Dimer en_US
dc.type Article en_US
dc.contributor.department Dept. of Biology en_US
dc.identifier.sourcetitle Journal of Molecular Biology en_US
dc.publication.originofpublisher Foreign en_US


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