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Structure of human phagocyte NADPH oxidase in the resting state

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 tran...

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Autores principales: Liu, Rui, Song, Kangcheng, Wu, Jing-Xiang, Geng, Xiao-Peng, Zheng, Liming, Gao, Xiaoyin, Peng, Hailin, Chen, Lei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9711523/
https://www.ncbi.nlm.nih.gov/pubmed/36413210
http://dx.doi.org/10.7554/eLife.83743
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author Liu, Rui
Song, Kangcheng
Wu, Jing-Xiang
Geng, Xiao-Peng
Zheng, Liming
Gao, Xiaoyin
Peng, Hailin
Chen, Lei
author_facet Liu, Rui
Song, Kangcheng
Wu, Jing-Xiang
Geng, Xiao-Peng
Zheng, Liming
Gao, Xiaoyin
Peng, Hailin
Chen, Lei
author_sort Liu, Rui
collection PubMed
description 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 heterodimer formation. Dehydrogenase (DH) domain of NOX2 in the resting state is not optimally docked onto the transmembrane domain, leading to inefficient electron transfer and NADPH binding. Structural analysis suggests that the cytosolic factors might activate the NOX2-p22 complex by stabilizing the DH in a productive docked conformation.
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spelling pubmed-97115232022-12-01 Structure of human phagocyte NADPH oxidase in the resting state Liu, Rui Song, Kangcheng Wu, Jing-Xiang Geng, Xiao-Peng Zheng, Liming Gao, Xiaoyin Peng, Hailin Chen, Lei eLife Immunology and Inflammation 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 heterodimer formation. Dehydrogenase (DH) domain of NOX2 in the resting state is not optimally docked onto the transmembrane domain, leading to inefficient electron transfer and NADPH binding. Structural analysis suggests that the cytosolic factors might activate the NOX2-p22 complex by stabilizing the DH in a productive docked conformation. eLife Sciences Publications, Ltd 2022-11-22 /pmc/articles/PMC9711523/ /pubmed/36413210 http://dx.doi.org/10.7554/eLife.83743 Text en © 2022, Liu, Song et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Liu, Rui
Song, Kangcheng
Wu, Jing-Xiang
Geng, Xiao-Peng
Zheng, Liming
Gao, Xiaoyin
Peng, Hailin
Chen, Lei
Structure of human phagocyte NADPH oxidase in the resting state
title Structure of human phagocyte NADPH oxidase in the resting state
title_full Structure of human phagocyte NADPH oxidase in the resting state
title_fullStr Structure of human phagocyte NADPH oxidase in the resting state
title_full_unstemmed Structure of human phagocyte NADPH oxidase in the resting state
title_short Structure of human phagocyte NADPH oxidase in the resting state
title_sort structure of human phagocyte nadph oxidase in the resting state
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9711523/
https://www.ncbi.nlm.nih.gov/pubmed/36413210
http://dx.doi.org/10.7554/eLife.83743
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