@article {2024|2169,
	title = {Structural profiles of the full phagocyte NADPH oxidase unveiled by combining computational biology and experimental knowledge},
	journal = {J. Biol. Chem.},
	volume = {300},
	year = {2024},
	pages = {107943},
	abstract = {<p>The phagocyte NADPH oxidase (NOX2) is an enzyme, crucial for innate immune defense, producing reactive oxygen species necessary for pathogen destruction. Its activation requires the assembly of soluble proteins (p47phox, p40phox, p67phox, and Rac) with the membrane-bound flavocytochrome b558 (cytb558). We combined circular-dichroism analyses, with decades of experimental data, to filter structural models of the NADPH oxidase complex generated by the artificial intelligence program AlphaFold2 (AF2). The predicted patterns tend to closely resemble the active states of the proteins, as shown by the compact structure of the cytb558, whose dehydrogenase domain is stabilized closer to the membrane. The modeling of the interaction of p47phox with cytb558, which is the initial assembly and activation steps of the NADPH oxidase, enables us to describe how the C terminus of p47phox interacts with the cytb558. Combining the AF2 cytb558-p47phox model and its classical molecular dynamics simulations, we highlighted new hydrophobic lipid insertions of p47phox, particularly at residues Trp80-Phe81 of its PX domain. The AF2 models also revealed the implications of intrinsically disordered regions, such as the fragment between the PX domain and the SH3 regions of p47phox, in ensuring distant protein-protein and membrane-protein interactions. Finally, the AF2 prediction of the cytb558-Trimera model highlighted the importance of leaving Rac1 as a separate protein to reach an active state of the NADPH oxidase complex. Altogether, our step-by-step approach provides a structural model of the active complex showing how disordered regions and specific lipid and protein interactions can enable and stabilize the multisubunit assembly.</p>
},
	keywords = {alphafold, Circular Dichroism, Computational biology, lipid-protein interaction, membrane protein, molecular modeling, NADPH oxidase, NOX2, p47(phox), p67(phox), protein assembly, trimera},
	author = {Aimeur, Sana and Fas, Burcu Aykac and Serfaty, Xavier and Santuz, Hubert and S Sacquin-Mora and Bizouarn, Tania and Taly, Antoine and Baciou, Laura}
}
@mastersthesis {2011|1574,
	title = {Coarse-grain models for proteins: Mechanical properties and interactions},
	year = {2011},
	note = {HDR d{\'e}livr{\'e}e par l{\textquoteright}UFR Sciences du Vivant},
	month = {dec},
	school = {Universit{\'e} Paris-Diderot - Paris VII},
	type = {phdHabilitation {\`a} diriger des recherches},
	keywords = {Computational biology, docking, elastic networks, interactions prot{\'e}iques, m{\'e}canique des prot{\'e}ines, Mod{\'e}lisation mol{\'e}culaire, protein interactions, protein mechanics, r{\'e}seau {\'e}lastique},
	url = {https://tel.archives-ouvertes.fr/tel-00652917},
	author = {S Sacquin-Mora}
}
