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Identification of Functional Subclasses in the DJ-1 Superfamily Proteins

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Identification of Functional Subclasses in the DJ-1 Superfamily Proteins University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Biochemistry -- Faculty Publications Biochemistry, Department of 1-2007 Identification of unctionalF Subclasses in the DJ-1 Superfamily Proteins Ying Wei Northeastern University, Dagmar Ringe University of Nebraska - Lincoln Mark A. Wilson Brandeis University, [email protected] Mary Jo Ondrechen Northeastern University, Follow this and additional works at: https://digitalcommons.unl.edu/biochemfacpub Part of the Biochemistry, Biophysics, and Structural Biology Commons Wei, Ying; Ringe, Dagmar; Wilson, Mark A.; and Ondrechen, Mary Jo, "Identification of unctionalF Subclasses in the DJ-1 Superfamily Proteins" (2007). Biochemistry -- Faculty Publications. 25. https://digitalcommons.unl.edu/biochemfacpub/25 This Article is brought to you for free and open access by the Biochemistry, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Biochemistry -- Faculty Publications by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Identification of Functional Subclasses in the DJ-1 Superfamily Proteins Ying Wei1,2, Dagmar Ringe3,4,5*, Mark A. Wilson3,4,5¤, Mary Jo Ondrechen1,2 1 Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, United States of America, 2 Institute for Complex Scientific Software, Northeastern University, Boston, Massachusetts, United States of America, 3 Department of Biochemistry, Brandeis University, Waltham, Massachusetts, United States of America, 4 Department of Chemistry, Brandeis University, Waltham, Massachusetts, United States of America, 5 Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, United States of America 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. Citation: Wei Y, Ringe D, Wilson MA, Ondrechen MJ (2007) Identification of functional subclasses in the DJ-1 superfamily proteins. PLoS Comput Biol 3(1): e10. doi:10.1371/ journal.pcbi.0030010 Introduction fold. The types of reactions catalyzed by proteins having this fold are numerous and varied. Structural biology in the post-genome era faces the Conversely, two proteins may have completely different challenge of determination of function from 3-D structure, folds, but catalyze the same reaction, with the same residues the critical next step toward the realization of the promises of and configurations in the active site. A good example is the 3 genomics. On the order of 10 protein structures in the set of pyridoxal phosphate–dependent transaminases of fold Protein Data Bank (PDB) are annotated as ‘‘hypothetical’’ or types I and II. These proteins catalyze the same reaction, with of ‘‘unknown function,’’ andthisnumberisincreasing active sites that are practically identical, but the two folds are dramatically as structural genomics initiatives deposit large completely different. numbers of structures in the PDB. Functional annotation is In addition, the important residues in an enzyme active site usually dependent on sequence similarity to identify proteins may not be obvious. Many reactions in biology may be that are expected to be similar in structure and therefore may characterized by the steps required to bring about any be similar in function. Even when sequence comparison fails chemical transformation. The catalytic entities involved in to find a closely related protein, the overall structural fold still may be similar to one that is already known. Such structural relationships, however, still do not necessarily Editor: Luhua Lai, Peking University, China identify a functional relationship. The reason for the Received September 11, 2006; Accepted December 7, 2006; Published January discrepancy is that currently there is not adequate under- 26, 2007 standing of the relationship between macromolecular struc- Copyright: Ó 2007 Wei at al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted ture and function for most proteins. Thus, structural use, distribution, and reproduction in any medium, provided the original author similarity in many cases has proved to be a poor guide to and source are credited. function. Many proteins with similar and recognizable folds Abbreviations: PDB, Protein Data Bank; THEMATICS, theoretical microscopic have completely different functions, even sometimes when titration curves there is sufficient sequence similarity to consider them * To whom correspondence should be addressed. E-mail: [email protected] ‘‘homologous.’’ The best examples of this principle are the ¤ Current address: Department of Biochemistry, University of Nebraska, Lincoln, enzymes having the TIM (triosephosphate isomerase) barrel Nebraska, United States of America PLoS Computational Biology | www.ploscompbiol.org0120 January 2007 | Volume 3 | Issue 1 | e10 Functional Classification for DJ-1 Proteins Author Summary arrangements of these residues. We compare THEMATICS predictions with the experimental evidence that is currently Genome sequencing has led to the discovery of many new gene available and argue that these structurally similar proteins fall products, proteins. These discoveries hold tremendous potential for into at least three distinct functional classes. totally new approaches to the diagnosis and treatment of disease. The catalytic power of an enzyme relies not only on the To realize this potential, one important step is to understand the nature of the residues that aid catalysis, but also on their function of the thousands of proteins whose function is currently position relative to the substrate. The method that identifies unknown. One of these proteins of unknown function is human DJ- 1, a protein that appears to play a protective role against Parkinson residues in the active site of a structure therefore also locates and other neurodegenerative diseases. Here we present a computa- their relative positions and defines the type of chemistry that tional approach to the classification by function of DJ-1 and its is possible, and potentially the substrate that can be family members. Eight DJ-1 family members, all with similar 3-D recognized. Here we show that the arrangements in space structure, are analyzed. Three different probable functional classes of the residues predicted by our method form structural emerge from this analysis on six of the family members, all with a motifs from which one can deduce important clues about simple calculation. functionality. We illustrate the principle with a set of structurally similar proteins with different probable func- each step, such as acids or bases, can be inferred from the tions. Our predictions enable the similar structures to be known chemistry. Residues that can play these roles are well- sorted into distinct functional categories. defined; however, it is not so easy to determine which particular residues in a given protein are actually playing Results these roles. Ideally, a structure with substrate bound would resolve the question, but such structures are rarely available A search [9] for structures similar to DJ-1 was performed, for proteins of unknown function. Therefore, another and 11 structures with a Dali Z score of 15 or higher and an method is needed to identify residues involved in catalysis RMSD of 2.3 or less were chosen. The next closest proteins and
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