The 1.1-Å resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease

Abstract

Mutations in DJ-1, a human gene with homologues in organisms from all kingdoms of life, have been shown to be associated with autosomal recessive, early onset Parkinson's disease (PARK7). We report here the three-dimensional structure of the DJ-1 protein, determined at a resolution of 1.1 Å by x-ray crystallography. The chain fold of DJ-1 resembles those of a bacterial protein, PfpI, that has been annotated as a cysteine protease, and of a domain of a bacterial catalase whose role in the activity of that enzyme is uncertain. In contrast to PfpI, a hexameric protein whose oligomeric structure is essential for its putative proteolytic activity, DJ-1 is a dimer with completely different intersubunit contacts. The proposed catalytic triad of PfpI is absent from the corresponding region of the structure of DJ-1, and biochemical assays fail to detect any protease activity for purified DJ-1. A highly conserved cysteine residue, which is catalytically essential in homologues of DJ-1, shows an extreme sensitivity to radiation damage and may be subject to other forms of oxidative modification as well. The structure suggests that the loss of function caused by the Parkinson's-associated mutation L166P in DJ-1 is due to destabilization of the dimer interface. Taken together, the crystal structure of human DJ-1 plus other observations suggest the possible involvement of this protein in the cellular oxidative stress response and a general etiology of neurodegenerative diseases.

Fermentation and alternative respiration compensate for NADH dehydrogenase deficiency in a prokaryotic model of DJ-1-associated Parkinsonism

“…The crystal structures of YajL and DJ-1 are strikingly similar (Wilson et al, 2003(Wilson et al, , 2005, and their backbone structures are essentially identical (0.9 Å C a root-mean-square deviation), suggesting that they have similar functions. DJ-1 is involved in the cellular response to oxidative stress, and has been suggested to function as a weak protease (Lee et al, 2003), an oxidative stress-activated chaperone Shendelman et al, 2004;Zhou et al, 2006), an atypical peroxiredoxin-like peroxidase (Andres-Mateos et al, 2007;Canet-Avilés et al, 2004), a stabilizer of the antioxidant transcriptional regulator Nrf2 (Clements et al, 2006), an apoptosis inhibitor via interaction with Daxx (Junn et al, 2005), a transcriptional or translational regulator of gene expression (Cookson, 2005; van der Brug et al, 2008) and a regulator of uncoupling protein expression affecting the production of reactive oxygen species (Guzman et al, 2010).…”

Cysteine pKa Depression by a Protonated Glutamic Acid in Human DJ-1

“…The structure of orthorhombic wtDJ-1 was determined by molecular replacement with human DJ-1 (PDB entry 1P5F) (25) as a search model in PHASER (32) as implemented in the CCP4 suite of programs (33). The structures of E18L, E18Q, E18D, and E18N DJ-1 in space group P3 1 21 were refined using human DJ-1 (1P5F) as the starting model (25). Diffraction data that extend to atomic resolution (d min e 1.2 Å) were collected for orthorhombic wt, E18L, and E18D DJ-1, while the data for E18Q and E18N DJ-1 were of lower resolution at 1.35 and 1.6 Å, respectively.…”

“…Crystal structures determined by several independent groups (21)(22)(23)(24)(25) show that C106 is located at a solventexposed sharp bend between a -strand and an R-helix called the "nucleophile elbow" (26). The backbone φ and ψ angles for the nucleophile elbow cysteine fall in the unfavorable region of Ramachandran space for every structurally characterized member of the DJ-1 superfamily (27), possibly contributing to its reactivity.…”

Familial Parkinson's Disease-associated L166P Mutation Disrupts DJ-1 Protein Folding and Function

“…We and other groups have recently solved the crystal structure of human DJ-1, which shows that DJ-1 adopts a helix-strand-helix sandwich structure similar to the bacterial protease PH1704 and Escherichia coli chaperone protein Hsp31 (25)(26)(27)(28)(29). However, it is unclear whether DJ-1 has a protease or chaperone function because the Cys-His-(Glu/Asp) catalytic triad and the quaternary structure of PH1704 and Hsp31 are not conserved in DJ-1.…”