Duox1 (Mus musculus, UniProtKB:A2AQ92) — Curation Notes

2026-10-27 — Mouse ortholog review paired with human DUOX1 (Q9NRD9)

Benchmark identity and orthology

UniProtKB:A2AQ92 (DUOX1_MOUSE, MGI:2139422, 1551 aa) is the reviewed canonical entry for mouse Dual oxidase 1 (Duox1). It is the 1:1 ortholog of human DUOX1 (UniProtKB:Q9NRD9, 1551 aa) in PANTHER subfamily PTHR11972:SF75 (DUAL OXIDASE 1), alongside rat Q8CIY2, pig Q8HZK3, and dog Q9MZF4. Its sister paralog Duox2 sits in PTHR11972:SF67, and C. elegans bli-3 (O61213) sits in PTHR11972:SF175.

Direct mouse experimental evidence

  1. Cryo-EM structures and catalytic mechanism (PMID:32929281(https://pubmed.ncbi.nlm.nih.gov/32929281/)):
  2. Sun (2020) solved cryo-EM structures of the mouse DUOX1–DUOXA1 complex in NADPH-free, NADPH-bound, and dimer-of-dimers states (PDB:6WXR, PDB:6WXU, PDB:6WXV) [PMID:32929281, "Here I report cryo-EM structures of mouse DUOX1–DUOXA1 complexes in NADPH-free, NADPH-bound and dimer-of-dimer states, providing structural mechanisms underlying DUOX1–DUOXA1 activation and regulation and molecular insights into ROS production."].
  3. Peroxidase-homology domain (PHD) lacks heme and peroxidase activity: Although the extracellular N-terminal PHD (residues 26–593) adopts a peroxidase fold (RMSD 1.3 Å to bovine LPO), no heme density is present in the cryo-EM map and the histidines required for heme coordination are missing [PMID:32929281, "Though the PHD of DUOX1 has an overall architecture of peroxidase with an RMSD of 1.3 Å when superimposed with the bovine lactoperoxidase (LPO, PDB 5B72) (Extended Data Fig. 2a)21, the facts that no heme density is observed in the cryo-EM map and histidines needed for heme coordination are missing in the putative binding pocket strongly suggest that the PHD domain of DUOX1 lacks heme-dependent peroxidase activity."]. Instead, the PHD binds a structural $\text{Ca}^{2+}$ ion at Glu109/Asp170/Asn172/Asp174/Trp176 and mediates extensive extracellular contacts with DUOXA1 and across the dimer-of-dimers interface.
  4. Transmembrane heme and cytosolic FAD/NADPH electron transfer pathway: Two heme groups are sandwiched orthogonally in the transmembrane helices S2–S5 (HEME #1 coordinated by His1144 and His1238; HEME #2 coordinated by His1130 and His1225), FAD binds at the positively charged interface between the TMD and cytoplasmic dehydrogenase domain, and NADPH binds at the TMD–NBD interface, defining the electron transfer relay $\text{NADPH} \rightarrow \text{FAD} \rightarrow \text{HEME #2} \rightarrow \text{Phe1097} \rightarrow \text{HEME #1} \rightarrow \text{O}_2$ to generate $\text{H}_2\text{O}_2$, with Phe1097 mutagenesis reducing $\text{H}_2\text{O}_2$ output [PMID:32929281, "One possible electron transfer pathway was identified as follows: NADPH → FAD → HEME #2 → Phe1097 → HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f)."].

  5. Oligomerization state: The active unit is the 1:1 DUOX1–DUOXA1 heterodimer, whereas the heterotetrameric dimer-of-dimers represents an autoinhibited state in which intracellular domain flexibility blocks electron transfer [PMID:32929281, "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."].

  6. In vivo antiviral innate immunity (PMID:34168077(https://pubmed.ncbi.nlm.nih.gov/34168077/)):

  7. Sarr et al. (2021) demonstrated that Duox1-/- mice challenged intranasally with influenza A virus exhibit increased mortality and morbidity, impaired lung viral clearance, altered airway cytokine profiles (IL-1β, IL-2, CCL1, CCL3, CCL11, CCL19, CCL20, CCL27, CXCL5, CXCL11), impaired innate leukocyte recruitment, and elevated airway epithelial apoptosis [PMID:34168077, "Upon influenza airway challenge, Duox1-/- mice have enhanced mortality, morbidity, and impaired lung viral clearance."]. Uninfected Duox1-/- lungs also have reduced basal $\text{H}_2\text{O}_2$ levels in bronchoalveolar lavage fluid.

  8. Neural stem cell ROS production with Nip1/Duoxa1 (PMID:20233719(https://pubmed.ncbi.nlm.nih.gov/20233719/)):

  9. Kennedy et al. (2010) showed that Nip1 (Duoxa1, UniProtKB:Q8VE49) interacts with Duox1 at the plasma membrane of differentiating P19 neural stem cells and mediates Duox1-dependent ROS production [PMID:20233719, "The highest expression of Nip1 was observed in undifferentiated neuronal stem cells and was associated with Duox1-mediated reactive oxygen species ROS production."].

Summary of annotation decisions (68 reviewed rows from 69 GOA rows)