3b38 | pdb_00003b38

Structure of A104V DJ-1

spinqualitylabelsall models 3b38, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3b38 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO Related: 2rk3, 2rk4, 2rk6, 3b36 Gene: PARK7 (HUMAN) 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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed A number of missense mutations in the oxidative stress response protein DJ-1 are implicated in rare forms of familial Parkinsonism. The best-characterized Parkinsonian DJ-1 missense mutation, L166P, disrupts homodimerization and results in a poorly folded protein. The molecular basis by which the other Parkinsonism-associated mutations disrupt the function of DJ-1, however, is incompletely understood. In this study we show that three different Parkinsonism-associated DJ-1 missense mutations (A104T, E163K, and M26I) reduce the thermal stability of DJ-1 in solution by subtly perturbing the structure of DJ-1 without causing major folding defects or loss of dimerization. Atomic resolution X-ray crystallography shows that the A104T substitution introduces water and a discretely disordered residue into the core of the protein, E163K disrupts a key salt bridge with R145, and M26I causes packing defects in the core of the dimer. The deleterious effect of each Parkinsonism-associated mutation on DJ-1 is dissected by analysis of engineered substitutions (M26L, A104V, and E163K/R145E) that partially alleviate each of the defects introduced by the A104T, E163K and M26I mutations. In total, our results suggest that the protective function of DJ-1 can be compromised by diverse perturbations in its structural integrity, particularly near the junctions of secondary structural elements. Structural Impact of Three Parkinsonism-Associated Missense Mutations on Human DJ-1(,).,Lakshminarasimhan M, Maldonado MT, Zhou W, Fink AL, Wilson MA Biochemistry. 2008 Feb 5;47(5):1381-92. Epub 2008 Jan 9. PMID:18181649 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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