STRUCTURAL STUDIES OF MEMBERS OF THE DJ-1 SUPERFAMILY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The DJ-1 superfamily is a large and diverse set of proteins that has representatives in most kingdoms of life. Human DJ-1 is protein that protects cells against oxidative stress, and in implicated in both Parkinson?s disease and certain types of cancer. Many other members of the DJ-1 superfamily have been partially characterized and play important roles in the response of various organisms to environmental stress. We are interested in determining 1) how related but functionally distinct proteins in the DJ-1 superfamily use the similar structural features to fulfill different biological roles and 2) how posttranslational modifications regulate the functions of these proteins. We are studying DJ-1 from several species (Human, Drosophila melanogaster, Escherichia coli), a related protein from Pseudomomas fluorescens that functions as an isonitrile hydratase, and several general stress response proteins in the DJ-1 superfamily. We and our collaborators have shown that the Drosophila melanogaster and E. coli DJ-1 homologues are functionally interchangeable with the human protein, and will use structural information to determine how these disease-related proteins are regulated. In a related project, we have shown that isonitrile hydratase catalyzes the conversion of various isonitriles to amides and employs amino acids that are well-conserved in the DJ-1 superfamily to accomplish this unique chemistry. We are also investigating the structures of an unusual clade of plant-specific DJ-1 proteins that are composed of two fused DJ-1-like domains. We have collected datasets on crystals of each of these proteins using the rotating anode source at UNL. Each of these structures has been successfully solved by molecular replacement and the improved data that we will collect at the APS will aid in model refinement, analysis, and publication.