STUDIES ON STRUCTURAL HOMOLOGUES, PUTIDAREDOXIN REDUCTASE & APOPTOSIS INDUCING F

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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. A crystallographic approach will be used to determine three-dimensional structures and study structure/function relationships in two structurally homologous FAD-containing enzymes, putidaredoxin reductase (Pdr) from Pseudomonas putida and apoptosis inducing factor (AIF) from mice. Both flavoproteins have a glutathione reductase fold and are bifunctional. Pdr catalyzes electron transfer from NADH to an iron-sulfur protein, putidaredoxin, in cytochrome P450cam monooxygenase, but it also has redox active cysteines and can function as dithiol/disulfide oxidoreduction. AIF is a phylogenetically old mammalian, caspase-independent death effector which, upon apoptosis induction, translocates from its normal localization, the mitochondrial intermembrane space, to the nucleus where it causes chromatin condensation and DNA fragmentation. Neither physiological function nor mechanism of apoptosis induced by this protein is known. Our research addresses the question of how the structures of Pdr and AIF are related to their catalytic function.