3B36

Structure of M26L DJ-1

Summary for 3B36

• Entry DOI: 10.2210/pdb3b36/pdb
• Related: 2RK3 2RK4 2RK6
• Descriptor: Protein DJ-1, CHLORIDE ION, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: parkinson's disease, pfpi, thij, chaperone, cytoplasm, disease mutation, nucleus, oncogene, oxidation, parkinson disease, phosphorylation, polymorphism, ubl conjugation
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q99497
• Total number of polymer chains: 1
• Total formula weight: 20713.29

Authors

Lakshminarasimhan, M.,Maldonado, M.T.,Zhou, W.,Fink, A.L.,Wilson, M.A. (deposition date: 2007-10-19, release date: 2008-01-15, Last modification date: 2023-08-30)

Primary citation

Lakshminarasimhan, M.,Maldonado, M.T.,Zhou, W.,Fink, A.L.,Wilson, M.A.
Structural Impact of Three Parkinsonism-Associated Missense Mutations on Human DJ-1.
Biochemistry, 47:1381-1392, 2008

PubMed Abstract: 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.

PubMed: 18181649
DOI: 10.1021/bi701189c

Experimental method

X-RAY DIFFRACTION (1.5 Å)