On the Oligomeric State of DJ1 Protein and Its Mutants Associated with Parkinson Disease: A COMBINED COMPUTATIONAL AND IN VITRO STUDY (original) (raw)

2007, Journal of Biological Chemistry

Here we use computational methods and biological assays to investigate the relationship between DJ-1 missense mutations and the protein oligomeric state. Molecular dynamics (MD) calculations suggest that: (i) the structure of DJ-1 wild-type (WT) in aqueous solution, in both oxidized and reduced forms, is similar to the crystal structure of the reduced form (3, 4); (ii) the PD-causing M26I variant is structurally similar to the WT, consistent with the experimental evidence showing the protein is a dimer as WT ((5-7) and in this work); (iii) R98Q is structurally similar to the WT, consistent with the fact that this is a physiological variant (8); (iv) the L166P monomer rapidly evolves towards a conformation significantly different than WT, suggesting a change in its ability to oligomerize (3, 4). Our combined computational and experimental approach is next used to identify a mutant (R28A) that, in contrast to L166P, destabilizes the dimer subunit-subunit interface without significantly changing secondary structure elements.