Identification of functional subclasses in the DJ-1 superfamily proteins - PubMed (original) (raw)

Identification of functional subclasses in the DJ-1 superfamily proteins

Ying Wei et al. PLoS Comput Biol. 2007.

Abstract

Genomics has posed the challenge of determination of protein function from sequence and/or 3-D structure. Functional assignment from sequence relationships can be misleading, and structural similarity does not necessarily imply functional similarity. Proteins in the DJ-1 family, many of which are of unknown function, are examples of proteins with both sequence and fold similarity that span multiple functional classes. THEMATICS (theoretical microscopic titration curves), an electrostatics-based computational approach to functional site prediction, is used to sort proteins in the DJ-1 family into different functional classes. Active site residues are predicted for the eight distinct DJ-1 proteins with available 3-D structures. Placement of the predicted residues onto a structural alignment for six of these proteins reveals three distinct types of active sites. Each type overlaps only partially with the others, with only one residue in common across all six sets of predicted residues. Human DJ-1 and YajL from Escherichia coli have very similar predicted active sites and belong to the same probable functional group. Protease I, a known cysteine protease from Pyrococcus horikoshii, and PfpI/YhbO from E. coli, a hypothetical protein of unknown function, belong to a separate class. THEMATICS predicts a set of residues that is typical of a cysteine protease for Protease I; the prediction for PfpI/YhbO bears some similarity. YDR533Cp from Saccharomyces cerevisiae, of unknown function, and the known chaperone Hsp31 from E. coli constitute a third group with nearly identical predicted active sites. While the first four proteins have predicted active sites at dimer interfaces, YDR533Cp and Hsp31 both have predicted sites contained within each subunit. Although YDR533Cp and Hsp31 form different dimers with different orientations between the subunits, the predicted active sites are superimposable within the monomer structures. Thus, the three predicted functional classes form four different types of quaternary structures. The computational prediction of the functional sites for protein structures of unknown function provides valuable clues for functional classification.

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Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Dimer Structures for Seven DJ-1 Family Members with the Two Subunits Shown in Red and Blue

(A) Human DJ-1; (B) YajL from E. coli; (C) Protease I from P. horikoshii; (D) YhbO from E. coli; (E) YDR533Cp from yeast; (F) Chaperone Hsp31 from E. coli; (G) the structural genomics putative Enhancing lycopene biosynthesis protein from E. coli. For all structures, the red subunits are oriented so that they are superimposable on each other. The relative positions of the blue subunits then illustrate the different types of dimer formation.

Figure 2

Figure 2. Ribbon Diagrams of Eight DJ-1 Family Proteins with Predicted Active Sites

(A) Human DJ-1; (B) YajL E. coli; (C) Protease I P. horikoshii; (D) YhbO E. coli; (E) YDR533Cp yeast; (F) Chaperone Hsp31 E. coli; (G) putative Enhancing lycopene biosynthesis protein E. coli; (H) APC35852 B. stearothermophilus. The subunit backbones are shown in yellow and green. Residues predicted by THEMATICS to be active site residues are shown in red (from the green subunit) and blue (from the yellow subunit).

Figure 3

Figure 3. Superpositions of the THEMATICS Predicted Active Site Residues (in Green and Magenta) for DJ-1 Family Members

(A) DJ-1 (magenta), YajL (green); (B) Protease I (magenta), YhbO (green); (C) Ydr533 (magenta), Hsp31 (green); (D) Ydr533 (magenta), APC35852 (green). The conserved cysteine residues that are not THEMATICS-positive residues are included for comparison purposes and are shown in yellow and red.

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