8KEI

Cryo-EM structure of NADPH oxidase 2 in complex with p22phox and EROS

Summary for 8KEI

• Entry DOI: 10.2210/pdb8kei/pdb
• EMDB information: 37159
• Descriptor: Cytochrome b-245 light chain, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, Cytochrome b-245 heavy chain, ... (10 entities in total)
• Functional Keywords: nadph oxidase, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 149160.66

Authors

Liang, S.Y.,Liu, A.J.,Liu, Y.Z.,Ye, R.D. (deposition date: 2023-08-11, release date: 2024-05-22, Last modification date: 2025-07-16)

Primary citation

Liang, S.,Liu, A.,Liu, Y.,Wang, F.,Zhou, Y.,Long, Y.,Wang, T.,Liu, Z.,Ren, R.,Ye, R.D.
Structural basis for EROS binding to human phagocyte NADPH oxidase NOX2.
Proc.Natl.Acad.Sci.USA, 121:e2320388121-e2320388121, 2024

PubMed Abstract: Essential for reactive oxygen species (EROS) protein is a recently identified molecular chaperone of NOX2 (gp91), the catalytic subunit of phagocyte NADPH oxidase. Deficiency in EROS is a recently identified cause for chronic granulomatous disease, a genetic disorder with recurrent bacterial and fungal infections. Here, we report a cryo-EM structure of the EROS-NOX2-p22 heterotrimeric complex at an overall resolution of 3.56Å. EROS and p22 are situated on the opposite sides of NOX2, and there is no direct contact between them. EROS associates with NOX2 through two antiparallel transmembrane (TM) α-helices and multiple β-strands that form hydrogen bonds with the cytoplasmic domain of NOX2. EROS binding induces a 79° upward bend of TM2 and a 48° backward rotation of the lower part of TM6 in NOX2, resulting in an increase in the distance between the two hemes and a shift of the binding site for flavin adenine dinucleotide (FAD). These conformational changes are expected to compromise superoxide production by NOX2, suggesting that the EROS-bound NOX2 is in a protected state against activation. Phorbol myristate acetate, an activator of NOX2 in vitro, is able to induce dissociation of NOX2 from EROS with concurrent increase in FAD binding and superoxide production in a transfected COS-7 model. In differentiated neutrophil-like HL-60, the majority of NOX2 on the cell surface is dissociated with EROS. Further studies are required to delineate how EROS dissociates from NOX2 during its transport to cell surface, which may be a potential mechanism for regulation of NOX2 activation.

PubMed: 38805284
DOI: 10.1073/pnas.2320388121

Experimental method

ELECTRON MICROSCOPY (3.56 Å)