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Structural basis of human NOX5 activation

Author

Listed:
  • 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)

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.

Suggested Citation

  • Chenxi Cui & Meiqin Jiang & Nikhil Jain & Sourav Das & Yu-Hua Lo & Ali A. Kermani & Tanadet Pipatpolkai & Ji Sun, 2024. "Structural basis of human NOX5 activation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48467-y
    DOI: 10.1038/s41467-024-48467-y
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    References listed on IDEAS

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    1. 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 Sesh, 2022. "Structure of the core human NADPH oxidase NOX2," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Jing-Xiang Wu & Rui Liu & Kangcheng Song & Lei Chen, 2021. "Structures of human dual oxidase 1 complex in low-calcium and high-calcium states," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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