Structure of the core human NADPH oxidase NOX2

Sigrid Noreng, Naruhisa Ota, Yonglian Sun, Hoangdung Ho, Matthew Johnson, Christopher P. Arthur, Kellen Schneider, Isabelle Lehoux, Christopher W. Davies, Kyle Mortara, Kit Wong, Dhaya Seshasayee, Matthieu Masureel (), Jian Payandeh (), Tangsheng Yi () and James T. Koerber ()
Additional contact information
Sigrid Noreng: Genentech Inc.
Naruhisa Ota: Genentech Inc.
Yonglian Sun: Genentech Inc.
Hoangdung Ho: Genentech Inc.
Matthew Johnson: Genentech Inc.
Christopher P. Arthur: Genentech Inc.
Kellen Schneider: Genentech Inc.
Isabelle Lehoux: Genentech Inc.
Christopher W. Davies: Genentech Inc.
Kyle Mortara: Genentech Inc.
Kit Wong: Genentech Inc.
Dhaya Seshasayee: Genentech Inc.
Matthieu Masureel: Genentech Inc.
Jian Payandeh: Genentech Inc.
Tangsheng Yi: Genentech Inc.
James T. Koerber: Genentech Inc.

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract NOX2 is the prototypical member of the NADPH oxidase NOX superfamily and produces superoxide (O2•−), 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.

Date: 2022
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DOI: 10.1038/s41467-022-33711-0

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