4s0z

Crystal structure of M26V human DJ-1

spinqualitylabelsall models 4s0z, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4s0z is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.45Å Ligands: ACT, EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PARK7_HUMAN Defects in PARK7 are the cause of Parkinson disease type 7 (PARK7) [MIM:606324. A neurodegenerative disorder characterized by resting tremor, postural tremor, bradykinesia, muscular rigidity, anxiety and psychotic episodes. PARK7 has onset before 40 years, slow progression and initial good response to levodopa. Some patients may show traits reminiscent of amyotrophic lateral sclerosis-parkinsonism/dementia complex (Guam disease). Function PARK7_HUMAN Protects cells against oxidative stress and cell death. Plays a role in regulating expression or stability of the mitochondrial uncoupling proteins SLC25A14 and SLC25A27 in dopaminergic neurons of the substantia nigra pars compacta and attenuates the oxidative stress induced by calcium entry into the neurons via L-type channels during pacemaking. Eliminates hydrogen peroxide and protects cells against hydrogen peroxide-induced cell death. May act as an atypical peroxiredoxin-like peroxidase that scavenges hydrogen peroxide. Following removal of a C-terminal peptide, displays protease activity and enhanced cytoprotective action against oxidative stress-induced apoptosis. Stabilizes NFE2L2 by preventing its association with KEAP1 and its subsequent ubiquitination. Binds to OTUD7B and inhibits its deubiquitinating activity. Enhances RELA nuclear translocation. Binds to a number of mRNAs containing multiple copies of GG or CC motifs and partially inhibits their translation but dissociates following oxidative stress. Required for correct mitochondrial morphology and function and for autophagy of dysfunctional mitochondria. Regulates astrocyte inflammatory responses. Acts as a positive regulator of androgen receptor-dependent transcription. Prevents aggregation of SNCA. Plays a role in fertilization. Has no proteolytic activity. Has cell-growth promoting activity and transforming activity. May function as a redox-sensitive chaperone. Publication Abstract from PubMed 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 degrees 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 degrees 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. Transient sampling of aggregation-prone conformations causes pathogenic instability of a parkinsonian mutant of DJ-1 at physiological temperature.,Milkovic NM, Catazaro J, Lin J, Halouska S, Kizziah JL, Basiaga S, Cerny RL, Powers R, Wilson MA Protein Sci. 2015 Oct;24(10):1671-85. doi: 10.1002/pro.2762. Epub 2015 Aug 17. PMID:26234586 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Protein DJ-1

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