Two in-press papers in the Journal of Biological Chemistry reveal the crystal structure of DJ-1, a protein of unknown function that was recently implicated in the etiology of familial Parkinson's disease (see ARF related news story).
Working independently, Xiao Tao and Liang Tong at Columbia University, New York, and Fuyuhiko Inagaki and colleagues at Hokkaido University, Sapporo, Japan, report the three-dimensional structure of the DJ-1 homodimer to resolutions of 1.8 and 1.95 Angstroms, respectively.
Both labs describe a similar overall structure, though Tao and Tong tally up a few more b-sheets (11 vs. 9) and one less a-helix (8 rather than 9) than reported by the Japanese group. First author Kazuya Honbou, from the latter, compared the 3D structure of DJ-1 with other GAT family proteins (Class I glutamine amidotransferases), revealing that DJ-1 has an extra a-helix at the C-terminal end of the molecule. This finding is supported by Tao and Tong. The two reports are also in agreement that DJ-1 is structurally most similar to an intracellular cysteine protease from Pyrococcus horikoshii, suggesting a proteolytic role for the protein, though as Ted Dawson from Johns Hopkins Medical Institute points out, the structural similarity to E. coli heat shock protein 31 suggests that DJ-1 may act as a chaperone.
Both groups also agree that the potential active site on DJ-1 is unlike those found in other GAT members, which have a catalytic triad of amino acids comprising a cysteine, a histidine, and an acidic residue, either glutamic or aspartic acid. Both groups identify cysteine 106 and histidine 126 as likely to be involved in catalysis, but both also fail to detect any acidic residue close enough to form the third leg of the triad. Honbou and colleagues speculate that the additional helix may be endowed with a regulatory role, and prevent the acidic residue from accessing the triad site, whereas in GAT family dimers, the acidic residue is supplied by the other half of the dimer. Alternatively, Tao and Tong suggest that the catalytic site may be a cysteine/histidine diad, as found in the caspases.
Of prime interest to the neurodegeneration field is the role played by leucine 166, which when mutated to proline causes Parkinson's disease. Tao and Tong suggest that the mutation, which lies in the middle of the seventh a-helix, not only would cause this part of the molecule to unfold, but would also destabilize the dimer by disrupting hydrophobic interactions between the two polypeptide chains. This is also the outcome predicted by Honobu and colleagues. Thus, it would seem that a dimer of DJ-1 is essential to prevent Parkinson's, though exactly what role the protein plays is still a mystery.—Tom Fagan
No Available Further Reading
- Tao X, Tong L. Crystal structure of human DJ-1, a protein associated with early onset Parkinson's disease. J Biol Chem. 2003 Aug 15;278(33):31372-9. PubMed.
- Honbou K, Suzuki NN, Horiuchi M, Niki T, Taira T, Ariga H, Inagaki F. The crystal structure of DJ-1, a protein related to male fertility and Parkinson's disease. J Biol Chem. 2003 Aug 15;278(33):31380-4. PubMed.