Please use this identifier to cite or link to this item: http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/9071
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dc.contributor.authorPAL, SUMANen_US
dc.contributor.authorUDGAONKAR, JAYANT B.en_US
dc.date.accessioned2024-09-06T10:42:10Z-
dc.date.available2024-09-06T10:42:10Z-
dc.date.issued2024-10en_US
dc.identifier.citationJournal of Molecular Biology, 436(09), 168736.en_US
dc.identifier.issn0022-2836en_US
dc.identifier.issn1089-8638en_US
dc.identifier.urihttps://doi.org/10.1016/j.jmb.2024.168736en_US
dc.identifier.urihttp://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/9071-
dc.description.abstractMisfolding 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.isoenen_US
dc.publisherElsevier B.V.en_US
dc.subjectPrion misfoldingen_US
dc.subjectPrion diseasesen_US
dc.subjectMouse prion proteinen_US
dc.subjectMolten globule formen_US
dc.subjectAromatic residuesen_US
dc.subject2024en_US
dc.subject2024-SEP-WEEK1en_US
dc.subjectTOC-SEP-2024en_US
dc.titleSlow Misfolding of a Molten Globule form of a Mutant Prion Protein Variant into a β-rich Dimeren_US
dc.typeArticleen_US
dc.contributor.departmentDept. of Biologyen_US
dc.identifier.sourcetitleJournal of Molecular Biologyen_US
dc.publication.originofpublisherForeignen_US
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