Structural impact of three Parkinsonism-associated missense mutations on human DJ-1

Mahadevan Lakshminarasimhan, Marien T. Maldonado, Wenbo Zhou, Anthony L. Fink, Mark A. Wilson

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1381-1392
Number of pages12
JournalBiochemistry
Volume47
Issue number5
DOIs
StatePublished - Feb 5 2008

ASJC Scopus subject areas

  • Biochemistry

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