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Structure of the core human NADPH oxidase NOX2
NOX2 is the prototypical member of the NADPH oxidase NOX superfamily and produces superoxide (O(2)(•−)), a key reactive oxygen species (ROS) that is essential in innate and adaptive immunity. Mutations that lead to deficiency in NOX2 activity correlate with increased susceptibility to bacterial and...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9568551/ https://www.ncbi.nlm.nih.gov/pubmed/36241643 http://dx.doi.org/10.1038/s41467-022-33711-0 |
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author | Noreng, Sigrid Ota, Naruhisa Sun, Yonglian Ho, Hoangdung Johnson, Matthew Arthur, Christopher P. Schneider, Kellen Lehoux, Isabelle Davies, Christopher W. Mortara, Kyle Wong, Kit Seshasayee, Dhaya Masureel, Matthieu Payandeh, Jian Yi, Tangsheng Koerber, James T. |
author_facet | Noreng, Sigrid Ota, Naruhisa Sun, Yonglian Ho, Hoangdung Johnson, Matthew Arthur, Christopher P. Schneider, Kellen Lehoux, Isabelle Davies, Christopher W. Mortara, Kyle Wong, Kit Seshasayee, Dhaya Masureel, Matthieu Payandeh, Jian Yi, Tangsheng Koerber, James T. |
author_sort | Noreng, Sigrid |
collection | PubMed |
description | NOX2 is the prototypical member of the NADPH oxidase NOX superfamily and produces superoxide (O(2)(•−)), a key reactive oxygen species (ROS) that is essential in innate and adaptive immunity. Mutations that lead to deficiency in NOX2 activity correlate with increased susceptibility to bacterial and fungal infections, resulting in chronic granulomatous disease. The core of NOX2 is formed by a heterodimeric transmembrane complex composed of NOX2 (formerly gp91) and p22, but a detailed description of its structural architecture is lacking. Here, we present the structure of the human NOX2 core complex bound to a selective anti-NOX2 antibody fragment. The core complex reveals an intricate extracellular topology of NOX2, a four-transmembrane fold of the p22 subunit, and an extensive transmembrane interface which provides insights into NOX2 assembly and activation. Functional assays uncover an inhibitory activity of the 7G5 antibody mediated by internalization-dependent and internalization-independent mechanisms. Overall, our results provide insights into the NOX2 core complex architecture, disease-causing mutations, and potential avenues for selective NOX2 pharmacological modulation. |
format | Online Article Text |
id | pubmed-9568551 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-95685512022-10-16 Structure of the core human NADPH oxidase NOX2 Noreng, Sigrid Ota, Naruhisa Sun, Yonglian Ho, Hoangdung Johnson, Matthew Arthur, Christopher P. Schneider, Kellen Lehoux, Isabelle Davies, Christopher W. Mortara, Kyle Wong, Kit Seshasayee, Dhaya Masureel, Matthieu Payandeh, Jian Yi, Tangsheng Koerber, James T. Nat Commun Article NOX2 is the prototypical member of the NADPH oxidase NOX superfamily and produces superoxide (O(2)(•−)), a key reactive oxygen species (ROS) that is essential in innate and adaptive immunity. Mutations that lead to deficiency in NOX2 activity correlate with increased susceptibility to bacterial and fungal infections, resulting in chronic granulomatous disease. The core of NOX2 is formed by a heterodimeric transmembrane complex composed of NOX2 (formerly gp91) and p22, but a detailed description of its structural architecture is lacking. Here, we present the structure of the human NOX2 core complex bound to a selective anti-NOX2 antibody fragment. The core complex reveals an intricate extracellular topology of NOX2, a four-transmembrane fold of the p22 subunit, and an extensive transmembrane interface which provides insights into NOX2 assembly and activation. Functional assays uncover an inhibitory activity of the 7G5 antibody mediated by internalization-dependent and internalization-independent mechanisms. Overall, our results provide insights into the NOX2 core complex architecture, disease-causing mutations, and potential avenues for selective NOX2 pharmacological modulation. Nature Publishing Group UK 2022-10-14 /pmc/articles/PMC9568551/ /pubmed/36241643 http://dx.doi.org/10.1038/s41467-022-33711-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Noreng, Sigrid Ota, Naruhisa Sun, Yonglian Ho, Hoangdung Johnson, Matthew Arthur, Christopher P. Schneider, Kellen Lehoux, Isabelle Davies, Christopher W. Mortara, Kyle Wong, Kit Seshasayee, Dhaya Masureel, Matthieu Payandeh, Jian Yi, Tangsheng Koerber, James T. Structure of the core human NADPH oxidase NOX2 |
title | Structure of the core human NADPH oxidase NOX2 |
title_full | Structure of the core human NADPH oxidase NOX2 |
title_fullStr | Structure of the core human NADPH oxidase NOX2 |
title_full_unstemmed | Structure of the core human NADPH oxidase NOX2 |
title_short | Structure of the core human NADPH oxidase NOX2 |
title_sort | structure of the core human nadph oxidase nox2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9568551/ https://www.ncbi.nlm.nih.gov/pubmed/36241643 http://dx.doi.org/10.1038/s41467-022-33711-0 |
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