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Poster De Conférence Année : 2023

MODELING THE NADPH OXIDASE (NOX) COMPLEX

Burcu Aykac-Fas
Marie Erard
Oliver Nüsse
Antoine Taly

Résumé

The phagocyte NADPH oxidase is a multicomponent enzyme that becomes active after the assembly of its cytosolic proteins p40phox, p47phox, p67phox; the small GTPase Rac, and transmembrane proteins p22phox and NOX2 (gp91phox). Upon activation, the cell signaling cascade triggers phosphorylations of the subunits of the cytosolic heterotrimeric complex, resulting in its conformational transition into the active state. The formation of the active complex also involves reorganizing the intramolecular interactions within the cytosolic complex and forming new interactions with the membrane subunits and anionic phospholipids in the membrane. The C-term of NOX2, as well as p47phox and p67phox, contain structured domains separated by intrinsically disordered regions (IDRs), and their flexibility is crucial for the activity of NOX. This work aims to model the NOX complex embedded in a physiologically relevant membrane and identify the protein-protein/protein-membrane interactions that form the basis of the oxidase assembly and functioning, including the modeling of the IDRs and the phosphorylations of its subunits, based on the NOX cytosolic complex and the membrane components. Therefore, an integrative structural biology approach is followed, combining deep learning-based modeling approaches for multimeric complexes, all-atom, and coarse-grained conventional molecular dynamics simulations, supported by constraints from our experimental partners. Thus, this combined approach will help us identify the key residues responsible for the enzyme activity and, possibly, potential therapeutic targets and will contribute to the understanding of the NADPH oxidase machinery at the atomic level.
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Dates et versions

hal-04112654 , version 1 (31-05-2023)

Identifiants

  • HAL Id : hal-04112654 , version 1

Citer

Burcu Aykac-Fas, Marie Erard, Oliver Nüsse, Sophie Sacquin-Mora, Antoine Taly. MODELING THE NADPH OXIDASE (NOX) COMPLEX. XXIIIème congrès du GGMM, May 2023, Toulouse, France. ⟨hal-04112654⟩
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