Structure of human phagocyte NADPH oxidase in the resting state
- Peking University, China
Abstract
Phagocyte oxidase plays an essential role in the first line of host defense against pathogens. It oxidizes intracellular NADPH to reduce extracellular oxygen to produce superoxide anions that participate in pathogen killing. The resting phagocyte oxidase is a heterodimeric complex formed by two transmembrane proteins NOX2 and p22. Despite the physiological importance of this complex, its structure remains elusive. Here we reported the cryo-EM structure of the functional human NOX2-p22 complex in nanodisc in the resting state. NOX2 shows a canonical 6-TM architecture of NOX and p22 has four transmembrane helices. M3, M4, and M5 of NOX2 and M1 and M4 helices of p22 are involved in the hetero-dimer formation. DH domain of NOX2 in the resting state is not optimally docked onto the transmembrane domain (TMD), leading to inefficient electron transfer and NADPH binding. Structural analysis suggests that the cytosolic factors might activate the NOX2-p22 complex by stabilizing the dehydrogenase domain (DH) in a productive docked conformation.
Data availability
Cryo-EM maps and atomic coordinate of the NOX2-p22-7D5-TP1170 complex have been deposited in the EMDB and PDB under the ID codes EMDB: EMD-34389 and PDB: 8GZ3.
Article and author information
Author details
Funding
National Key Research and Development Program of China (2022YFA1300088)
- Lei Chen
National Natural Science Foundation of China (91957201,31870833,31821091,52021006)
- Hailin Peng
- Lei Chen
Beijing National Laboratory for Molecular Sciences (BNLMS-CXTD-202001)
- Hailin Peng
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Axel T Brunger, Stanford University School of Medicine, Howard Hughes Medical Institute, United States
Version history
- Received: September 27, 2022
- Preprint posted: October 4, 2022 (view preprint)
- Accepted: November 21, 2022
- Accepted Manuscript published: November 22, 2022 (version 1)
- Version of Record published: November 30, 2022 (version 2)
Copyright
© 2022, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure of human phagocyte NADPH oxidase in the resting state
eLife 11:e83743.
https://doi.org/10.7554/eLife.83743
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