Structural and functional studies of the DJ-1/ThiJ/PfpI superfamily proteins from Staphylococcus aureus

Abstract

Staphylococcus aureus is one of the most common pathogen that causes various diseases ranging from mild infections, such as skin infections and food poisoning, to life threatening infections, such as sepsis, endocarditis, and toxic shock syndrome. However, S. aureus has adapted to circumvent therapeutic strategies by developing resistance to antibiotics and becoming problems. The DJ-1/ThiJ/PfpI superfamily is a group of proteins over diverse organisms. This superfamily includes versatile proteins, such as proteases, chaperones, heat shock proteins and human Parkinsons disease protein. SAV0551 and SAV1875, conserved proteins from S. aureus, are members of the DJ-1/ThiJ/PfpI superfamily. However, their structure and function remain unknown. Thus, to understand the function and activity mechanism of these proteins, the crystal structure of SAV0551 and SAV1875 from S. aureus was determined. Their conserved cysteine residue forms a catalytic triad with histidine and aspartate. In particular, cysteine in SAV1875 is spontaneously oxidized to Cys105-SO2H in the crystal structure. To study the oxidative propensity of Cys105 in SAV1875 and the corresponding functional differences with changes in cysteine oxidation state, the crystal structures of SAV1875 variants, E17N, E17D, C105D, and over-oxidized SAV1875 were determined. The overall fold of SAV1875 and SAV0551 is similar to that observed for the DJ-1/ThiJ/PfpI superfamily. We identified SAV1875 as a novel member of the YhbO-type subfamily exhibiting chaperone function and SAV0551 as a member of Hsp-type subfamily that has chaperone and glyoxalase function. The chaperone activity was based on the surface structure, but if SAV1875 is over-oxidized further with H2O2, its chaperone activity is eliminated.