| Summary: | The long-term goal of this study is to evaluate key changes that occurred as a result of evolution from bacteria to the human respiratory enzyme, Complex II. Complex II has been extensively studied to define its roles in both energy metabolism and cell survival, and it was the first enzyme identified as having a covalent flavin cofactor. However, recent research that identified several new assembly factors for Complex II, as well as previously unidentified functions in the bacterial homologs, has made it apparent that there is still much to learn about this vital complex. Complex II homologs in bacteria share striking structural and sequence similarity and provide a powerful model system for the study of the process of assembly and the mechanism of covalent flavinylation in the complex. Structural and biochemical techniques were utilized to explore important evolutionary changes in Complex II from bacteria to human in two specific aims. Aim 1 focused on identifying the role of an assembly factor suspected to have a role in both assembly and covalent flavin attachment, as well as to investigate the mechanism of covalent flavin attachment. Aim 2 focused on structural characterization of alternative assembly factors and binding partners predicted to indicate new functions of the complex. Accomplishment of these aims fills gaps in our understanding of Complex II function and informs about the mechanisms of covalent flavin attachment, the underpinnings of which are highly conserved from bacteria to complex mammals.
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