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Structures of mouse DUOX1-DUOXA1 provide mechanistic insights into enzyme activation and regulation.

ABSTRACT: 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.

SUBMITTER: Sun J

PROVIDER: S-EPMC7644671 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Structures of mouse DUOX1-DUOXA1 provide mechanistic insights into enzyme activation and regulation.

Sun Ji J

Nature structural & molecular biology 20200914 11

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 mamma ...[more]

PMID: 32929281

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Dataset Information

Structures of mouse DUOX1-DUOXA1 provide mechanistic insights into enzyme activation and regulation.

Publications

Structures of mouse DUOX1-DUOXA1 provide mechanistic insights into enzyme activation and regulation.

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