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

Nat Struct Mol Biol. 2020 Nov;27(11):1086-1093. doi: 10.1038/s41594-020-0501-x. Epub 2020 Sep 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cryoelectron Microscopy
  • Dual Oxidases / chemistry
  • Dual Oxidases / metabolism*
  • Dual Oxidases / ultrastructure
  • Enzyme Activation*
  • Mice
  • Models, Molecular
  • NADP / metabolism
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / ultrastructure
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / ultrastructure
  • Protein Conformation


  • DUOXA1 protein, mouse
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • NADP
  • Dual Oxidases
  • Duox1 protein, mouse