Structural basis of human NOX5 activation
Chenxi Cui,
Meiqin Jiang,
Nikhil Jain,
Sourav Das,
Yu-Hua Lo,
Ali A. Kermani,
Tanadet Pipatpolkai (tanadet.pipatpolkai@ntu.edu.sg) and
Ji Sun (ji.sun@stjude.org)
Additional contact information
Chenxi Cui: St Jude Children’s Research Hospital
Meiqin Jiang: St Jude Children’s Research Hospital
Nikhil Jain: St Jude Children’s Research Hospital
Sourav Das: St Jude Children’s Research Hospital
Yu-Hua Lo: St Jude Children’s Research Hospital
Ali A. Kermani: St Jude Children’s Research Hospital
Tanadet Pipatpolkai: Nanyang Technological University
Ji Sun: St Jude Children’s Research Hospital
Nature Communications, 2024, vol. 15, issue 1, 1-10
Abstract:
Abstract NADPH oxidase 5 (NOX5) catalyzes the production of superoxide free radicals and regulates physiological processes from sperm motility to cardiac rhythm. Overexpression of NOX5 leads to cancers, diabetes, and cardiovascular diseases. NOX5 is activated by intracellular calcium signaling, but the underlying molecular mechanism of which — in particular, how calcium triggers electron transfer from NADPH to FAD — is still unclear. Here we capture motions of full-length human NOX5 upon calcium binding using single-particle cryogenic electron microscopy (cryo-EM). By combining biochemistry, mutagenesis analyses, and molecular dynamics (MD) simulations, we decode the molecular basis of NOX5 activation and electron transfer. We find that calcium binding to the EF-hand domain increases NADPH dynamics, permitting electron transfer between NADPH and FAD and superoxide production. Our structural findings also uncover a zinc-binding motif that is important for NOX5 stability and enzymatic activity, revealing modulation mechanisms of reactive oxygen species (ROS) production.
Date: 2024
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48467-y
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DOI: 10.1038/s41467-024-48467-y
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