Structural basis of human NOX5 activation
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 under...
| Main Authors: | , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Online Access: | https://hdl.handle.net/10356/178825 |
| _version_ | 1826119019494637568 |
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| author | Cui, Chenxi Jiang, Meiqin Jain, Nikhil Das, Sourav Lo, Yu-Hua Kermani, Ali A. Pipatpolkai, Tanadet Sun, Ji |
| author2 | School of Physical and Mathematical Sciences |
| author_facet | School of Physical and Mathematical Sciences Cui, Chenxi Jiang, Meiqin Jain, Nikhil Das, Sourav Lo, Yu-Hua Kermani, Ali A. Pipatpolkai, Tanadet Sun, Ji |
| author_sort | Cui, Chenxi |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T04:53:12Z |
| format | Journal Article |
| id | ntu-10356/178825 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:53:12Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1788252024-07-08T15:34:52Z Structural basis of human NOX5 activation Cui, Chenxi Jiang, Meiqin Jain, Nikhil Das, Sourav Lo, Yu-Hua Kermani, Ali A. Pipatpolkai, Tanadet Sun, Ji School of Physical and Mathematical Sciences Physics Conformational transition Cryoelectron microscopy 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. Published version The computations were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at the PDC Center for High Performance Computing, KTH Royal Institute of Technology, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. This work was funded by the NIH (R01GM141357) and American Lebanese Syrian Associated Charities (ALSAC). 2024-07-08T05:26:56Z 2024-07-08T05:26:56Z 2024 Journal Article Cui, C., Jiang, M., Jain, N., Das, S., Lo, Y., Kermani, A. A., Pipatpolkai, T. & Sun, J. (2024). Structural basis of human NOX5 activation. Nature Communications, 15(1), 3994-. https://dx.doi.org/10.1038/s41467-024-48467-y 2041-1723 https://hdl.handle.net/10356/178825 10.1038/s41467-024-48467-y 38734761 2-s2.0-85192872744 1 15 3994 en Nature Communications © 2024 The Author(s). 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/ licenses/by/4.0/. application/pdf |
| spellingShingle | Physics Conformational transition Cryoelectron microscopy Cui, Chenxi Jiang, Meiqin Jain, Nikhil Das, Sourav Lo, Yu-Hua Kermani, Ali A. Pipatpolkai, Tanadet Sun, Ji Structural basis of human NOX5 activation |
| title | Structural basis of human NOX5 activation |
| title_full | Structural basis of human NOX5 activation |
| title_fullStr | Structural basis of human NOX5 activation |
| title_full_unstemmed | Structural basis of human NOX5 activation |
| title_short | Structural basis of human NOX5 activation |
| title_sort | structural basis of human nox5 activation |
| topic | Physics Conformational transition Cryoelectron microscopy |
| url | https://hdl.handle.net/10356/178825 |
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