Abstract
Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. They are involved in many crucial biological processes and human diseases, especially in thyroid diseases. DUOXs are protein complexes co-assembled from the catalytic DUOX subunits and the auxiliary DUOXA subunits and their activities are regulated by intracellular calcium concentrations. Here, we report the cryo-EM structures of human DUOX1-DUOXA1 complex in both high-calcium and low-calcium states. These structures reveal the DUOX1 complex is a symmetric 2:2 hetero-tetramer stabilized by extensive inter-subunit interactions. Substrate NADPH and cofactor FAD are sandwiched between transmembrane domain and the cytosolic dehydrogenase domain of DUOX. In the presence of calcium ions, intracellular EF-hand modules might enhance the catalytic activity of DUOX by stabilizing the dehydrogenase domain in a conformation that allows electron transfer.
Highlights
Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen
DUOX1–2 proteins are highly expressed in thyroid tissue and they catalyze the production of hydrogen peroxide, which is important for the biosynthesis of thyroid hormones[4]
We found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calciumactivated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay[11] (Fig. 1a–c)
Summary
Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. They are involved in many crucial biological processes and human diseases, especially in thyroid diseases. 1234567890():,; Reactive oxygen species (ROS) are oxygen-containing chemical species that are highly reactive, such as hydrogen peroxide and superoxide anion[1]. ROS can be generated by a class of dedicated enzymes called NADPH oxidase (NOX) in a highly regulated manner These enzymes are multi-pass transmembrane proteins that catalyze the reduction of extracellular or luminal oxygen by intracellular NADPH to generate superoxide anion or hydrogen peroxide. Because of the important role of DUOX in thyroid tissue, they are named thyroid oxidase[4]
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