4S0Z

Crystal structure of M26V human DJ-1

Summary for 4S0Z

• Entry DOI: 10.2210/pdb4s0z/pdb
• Related: 1P5F 2RK4 3B36
• Descriptor: Protein DJ-1, 1,2-ETHANEDIOL, ACETATE ION, ... (4 entities in total)
• Functional Keywords: dj-1/thij/pfpi superfamily, oxidative stress response, chaperone
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane ; Lipid-anchor : Q99497
• Total number of polymer chains: 1
• Total formula weight: 20474.58

Authors

Milkovic, N.M.,Wilson, M.A. (deposition date: 2015-01-07, release date: 2015-08-05, Last modification date: 2023-09-20)

Primary citation

Milkovic, N.M.,Catazaro, J.,Lin, J.,Halouska, S.,Kizziah, J.L.,Basiaga, S.,Cerny, R.L.,Powers, R.,Wilson, M.A.
Transient sampling of aggregation-prone conformations causes pathogenic instability of a parkinsonian mutant of DJ-1 at physiological temperature.
Protein Sci., 24:1671-1685, 2015

PubMed 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.

PubMed: 26234586
DOI: 10.1002/pro.2762

Experimental method

X-RAY DIFFRACTION (1.45 Å)