Evolutionary and functional relationships within the DJ1 superfamily

Abstract

Background: Inferences about protein function are often made based on sequence homology to other gene products of known activities. This approach is valuable for small families of conserved proteins but can be difficult to apply to large superfamilies of proteins with diverse function. In this study we looked at sequence homology between members of the DJ-1/ThiJ/PfpI superfamily, which includes a human protein of unclear function, DJ-1, associated with inherited Parkinson's disease.

Results: DJ-1 orthologs in a variety of eukaryotic species cluster together in a single group. The most closely related group is the bacterial ThiJ genes. These are kinases involved in the biosynthesis of thiamine, a function that has been dispensed with evolutionarily in most eukaryotes where thiamine is an essential nutrient. The similarity with other characterized members of the superfamily, including proteases, is more remote. This is congruent with the recently solved crystal structures that fail to demonstrate the presence of a catalytic triad required for protease activity.

Conclusion: DJ-1 may have evolved from the bacterial gene encoding ThiJ kinase. However, as this function has been dispensed with in eukaryotes it appears that the gene has been co-opted for another function.

Figure 1

Cladogram of the DJ-1/ThiJ/PfpI superfamily. Consensus maximum likelihood tree with branch distances corresponding to level of bootstrap support. Known structures are highlighted along with the corresponding PDB identifier. From this tree it is clear that the DJ-1 superfamily contains proteins with diverse functions and that the DJ-1 cluster is most similar to the ThiJ subgroup. Group labels are guided by the annotation of the constituent sequences (for more details see text). Unlabeled clusters had a majority of sequences with unknown or disparate function. Sequence identifiers and files for the construction of this tree can be found in the supplemental information. Numbers in parantheses indicate percentage identities; the first number identity within the group, the second is the identity with human DJ-1.

Figure 2

The DJ1 and ThiJ families Cladogram of the alignment of the sequences belonging to the ThiJ and DJ-1 subgroups. Bootstrap support for this neighbor-joining tree is labeled at the vertices and the sequences are identified by their species name and accession number. The eukaryotic DJ-1 family members are boxed in blue to highlight their distinctness from the bacterial ThiJ proteins.

Figure 3

Amino acid conservation of the DJ-1/ThiJ homologues Multiple alignment of sequences within the DJ-1/ThiJ family shows high homology and presence of a number of absolutely conserved amino acids. Bars below each residue indicate the degree of conservation. As in (a), the eukaryotic DJ-1 family is boxed in blue for clarity.

Figure 4