Structural Impact of Three Parkinsonism-Associated Missense Mutations on Human DJ-1

Journal Article · Wed May 20 04:00:00 EDT 2009 · Biochem. 47:1381,2008

OSTI ID:953073

Lakshminarasimhan, M; Maldonado, M T; Zhou, W; Fink, A L; Wilson, M A

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.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 953073
• Report Number(s): SLAC-REPRINT-2009-211
• Journal Information: Biochem. 47:1381,2008, Journal Name: Biochem. 47:1381,2008 Journal Issue: 5 Vol. 47
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
CRYSTALLOGRAPHY
DEFECTS
DIMERIZATION
MUTATIONS
Other
BIO
CHEM
PROTEINS
RESIDUES
RESOLUTION
STABILITY
WATER