Structural basis of human NOX5 activation.
Humans
NADPH Oxidase 5
/ metabolism
Molecular Dynamics Simulation
Cryoelectron Microscopy
Calcium
/ metabolism
NADP
/ metabolism
Flavin-Adenine Dinucleotide
/ metabolism
Superoxides
/ metabolism
Protein Binding
Reactive Oxygen Species
/ metabolism
Zinc
/ metabolism
Electron Transport
Enzyme Activation
Binding Sites
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 May 2024
11 May 2024
Historique:
received:
05
09
2023
accepted:
02
05
2024
medline:
12
5
2024
pubmed:
12
5
2024
entrez:
11
5
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38734761
doi: 10.1038/s41467-024-48467-y
pii: 10.1038/s41467-024-48467-y
doi:
Substances chimiques
NADPH Oxidase 5
EC 1.6.3.-
NOX5 protein, human
EC 1.6.3.-
Calcium
SY7Q814VUP
NADP
53-59-8
Flavin-Adenine Dinucleotide
146-14-5
Superoxides
11062-77-4
Reactive Oxygen Species
0
Zinc
J41CSQ7QDS
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3994Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : R01GM141357
Organisme : Vetenskapsrådet (Swedish Research Council)
ID : 2018-05973
Informations de copyright
© 2024. The Author(s).
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