On the oligomeric state of DJ-1 protein and its mutants associated with Parkinson Disease. A combined computational and in vitro study.
Mutations in the DJ-1 protein are present in patients suffering from familial Parkinson disease. Here we use computational methods and biological assays to investigate the relationship between DJ-1 missense mutations and the protein oligomeric state. Molecular dynamics 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; (ii) the Parkinson disease-causing M26I variant is structurally similar to the WT, consistent with the experimental evidence showing the protein is a dimer as WT; (iii) R98Q is structurally similar to the WT, consistent with the fact that this is a physiological variant; and (iv) the L166P monomer rapidly evolves toward a conformation significantly different from WT, suggesting a change in its ability to oligomerize. 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.
Herrera
Fernando E
FE
International School for Advanced Studies, INFM DEMOCRITOS, SISSA Unit, Italian Institute of Technology, Via Beirut 2-4, 34014 Trieste, Italy.
Zucchelli
Silvia
S
Jezierska
Aneta
A
Lavina
Zeno Scotto
ZS
Gustincich
Stefano
S
Carloni
Paolo
P
D000409:Alanine / Q000737:chemistry; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D020125:Mutation, Missense; D015513:Oncogene Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D011487:Protein Conformation; D000071617:Protein Deglycase DJ-1; D017433:Protein Structure, Secondary; D012984:Software; D013997:Time Factors
D003432:Cross-Linking Reagents; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D000409:Alanine