Structures of human dual oxidase 1 complex in low-calcium and high-calcium states

• Published in: Nature communications Vol. 12; no. 1; pp. 155 - 11
• Main Authors: Wu, Jing-Xiang, Liu, Rui, Song, Kangcheng, Chen, Lei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/45/173; 631/45/607/1168; 631/535/1258/1259; 82/16; 82/80; 82/83; Biological activity; Calcium; Calcium (extracellular); Calcium (intracellular); Calcium - metabolism; Calcium ions; Catalytic activity; Cell Membrane - metabolism; Cell Membrane - ultrastructure; Cryoelectron Microscopy; Dehydrogenase; Dehydrogenases; Domains; Dual Oxidases - chemistry; Dual Oxidases - genetics; EF-hand; Electron transfer; Electrons; Enzyme Activation; Enzyme Assays; Flavin-Adenine Dinucleotide - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Hydrogen peroxide; Intracellular; Membrane Proteins - chemistry; Membrane Proteins - genetics; Models, Molecular; multidisciplinary; NADP - metabolism; Oxygen; Protein Domains; Protein structure; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Science; Science (multidisciplinary); Substrates; Thyroid; Thyroid diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20466-9

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. Dual oxidases (DUOXs), assembled from the catalytic DUOX and the auxiliary DUOXA subunits, produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen in a calcium-activated manner. Here authors report the cryo-EM structures of human DUOX1-DUOXA1 complex in both high-calcium and low-calcium states.