Transient sampling of aggregation-prone conformations causes pathogenic instability of a parkinsonian mutant of DJ-1 at physiological temperature.

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 cros

SUBMITTER: Milkovic NM 

PROVIDER: S-EPMC4594666 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature