6WXR

CryoEM structure of mouse DUOX1-DUOXA1 complex in the absence of NADPH

Summary for 6WXR

• Entry DOI: 10.2210/pdb6wxr/pdb
• EMDB information: 21962
• Descriptor: Dual oxidase 1, Dual oxidase maturation factor 1, alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: membrane protein, nadph oxidase, ros production
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 2
• Total formula weight: 217173.73

Authors

Sun, J. (deposition date: 2020-05-11, release date: 2020-09-02, Last modification date: 2025-05-21)

Primary citation

Sun, J.
Structures of mouse DUOX1-DUOXA1 provide mechanistic insights into enzyme activation and regulation.
Nat.Struct.Mol.Biol., 27:1086-1093, 2020

PubMed 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.

PubMed: 32929281
DOI: 10.1038/s41594-020-0501-x

Experimental method

ELECTRON MICROSCOPY (3.2 Å)