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Structures of mouse DUOX1–DUOXA1 provide mechanistic insights into enzyme activation and regulation
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Structures of mouse DUOX1–DUOXA1 provide mechanistic insights into enzyme activation and regulation
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Journal Article
Structures of mouse DUOX1–DUOXA1 provide mechanistic insights into enzyme activation and regulation
2020
Overview
DUOX1, an NADPH oxidase family member, catalyzes the production of hydrogen peroxide. DUOX1 is expressed in various tissues, including the thyroid and respiratory tract, and plays a crucial role in processes such as thyroid hormone biosynthesis and innate host defense. DUOX1 co-assembles with its maturation factor DUOXA1 to form an active enzyme complex. However, the molecular mechanisms for activation and regulation of DUOX1 remain mostly unclear. Here, I present cryo-EM structures of the mammalian DUOX1–DUOXA1 complex, in the absence and presence of substrate NADPH, as well as DUOX1–DUOXA1 in an unexpected dimer-of-dimers configuration. These structures reveal atomic details of the DUOX1-DUOXA1 interaction, a lipid-mediated NADPH-binding pocket and the electron transfer path. Furthermore, biochemical and structural analyses indicate that the dimer-of-dimers configuration represents an inactive state of DUOX1–DUOXA1, suggesting an oligomerization-dependent regulatory mechanism. Together, my work provides structural bases for DUOX1–DUOXA1 activation and regulation.DUOX1 is an NADPH oxidase involved in thyroid hormone production and innate host defense. Cryo-EM structures of murine DUOX1 bound to maturation factor DUOXA1 provide insights into regulation and activation of this enzyme.
Publisher
Nature Publishing Group
Subject
