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• W1900899383 startingPage "1671" @default.
• W1900899383 abstract "Abstract Various missense mutations in the cytoprotective protein DJ‐1 cause rare forms of inherited parkinsonism. One mutation, M26I, diminishes DJ‐1 protein levels in the cell but does not result in large changes in the three‐dimensional structure or thermal stability of the protein. Therefore, the molecular defect that results in loss of M26I DJ‐1 protective function is unclear. Using NMR spectroscopy near physiological temperature, we found that the picosecond–nanosecond dynamics of wild‐type and M26I DJ‐1 are similar. In contrast, elevated amide hydrogen/deuterium exchange rates indicate that M26I DJ‐1 is more flexible than the wild‐type protein on longer timescales and that hydrophobic regions of M26I DJ‐1 are transiently exposed to solvent. Tryptophan fluorescence spectroscopy and thiol crosslinking analyzed by mass spectrometry also demonstrate that M26I DJ‐1 samples conformations that differ from the wild‐type protein at 37°C. These transiently sampled conformations are unstable and cause M26I DJ‐1 to aggregate in vitro at physiological temperature but not at lower temperatures. M26I DJ‐1 aggregation is correlated with pathogenicity, as the structurally similar but non‐pathogenic M26L mutation does not aggregate at 37°C. The onset of dynamically driven M26I DJ‐1 instability at physiological temperature resolves conflicting literature reports about the behavior of this disease‐associated mutant and illustrates the pitfalls of characterizing proteins exclusively at room temperature or below, as key aspects of their behavior may not be apparent." @default.
• W1900899383 created "2016-06-24" @default.
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• W1900899383 date "2015-08-17" @default.
• W1900899383 modified "2023-10-16" @default.
• W1900899383 title "Transient sampling of aggregation-prone conformations causes pathogenic instability of a parkinsonian mutant of DJ-1 at physiological temperature" @default.
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• W1900899383 doi "https://doi.org/10.1002/pro.2762" @default.
• W1900899383 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4594666" @default.
• W1900899383 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26234586" @default.
• W1900899383 hasPublicationYear "2015" @default.
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