| Structural highlights
8x2l is a 4 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 2.99Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
CY24A_HUMAN Defects in CYBA are a cause of chronic granulomatous disease autosomal recessive cytochrome-b-negative (ARCGD) [MIM:233690. Chronic granulomatous disease is a genetically heterogeneous disorder characterized by the inability of neutrophils and phagocytes to kill microbes that they have ingested. Patients suffer from life-threatening bacterial/fungal infections.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Function
CY24A_HUMAN Critical component of the membrane-bound oxidase of phagocytes that generates superoxide. Associates with NOX3 to form a functional NADPH oxidase constitutively generating superoxide.[10]
Publication Abstract from PubMed
Phagocyte NADPH oxidase, a protein complex with a core made up of NOX2 and p22 subunits, is responsible for transferring electrons from intracellular NADPH to extracellular oxygen(1). This process generates superoxide anions that are vital for killing pathogens(1). The activation of phagocyte NADPH oxidase requires membrane translocation and the binding of several cytosolic factors(2). However, the exact mechanism by which cytosolic factors bind to and activate NOX2 is not well understood. Here we present the structure of the human NOX2-p22 complex activated by fragments of three cytosolic factors: p47, p67 and Rac1. The structure reveals that the p67-Rac1 complex clamps onto the dehydrogenase domain of NOX2 and induces its contraction, which stabilizes the binding of NADPH and results in a reduction of the distance between the NADPH-binding domain and the flavin adenine dinucleotide (FAD)-binding domain. Furthermore, the dehydrogenase domain docks onto the bottom of the transmembrane domain of NOX2, which reduces the distance between FAD and the inner haem. These structural rearrangements might facilitate the efficient transfer of electrons between the redox centres in NOX2 and lead to the activation of phagocyte NADPH oxidase.
Structure of human phagocyte NADPH oxidase in the activated state.,Liu X, Shi Y, Liu R, Song K, Chen L Nature. 2024 Mar;627(8002):189-195. doi: 10.1038/s41586-024-07056-1. Epub 2024 , Feb 14. PMID:38355798[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dinauer MC, Pierce EA, Bruns GA, Curnutte JT, Orkin SH. Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease. J Clin Invest. 1990 Nov;86(5):1729-37. PMID:2243141 doi:http://dx.doi.org/10.1172/JCI114898
- ↑ de Boer M, de Klein A, Hossle JP, Seger R, Corbeel L, Weening RS, Roos D. Cytochrome b558-negative, autosomal recessive chronic granulomatous disease: two new mutations in the cytochrome b558 light chain of the NADPH oxidase (p22-phox). Am J Hum Genet. 1992 Nov;51(5):1127-35. PMID:1415254
- ↑ Dinauer MC, Pierce EA, Erickson RW, Muhlebach TJ, Messner H, Orkin SH, Seger RA, Curnutte JT. Point mutation in the cytoplasmic domain of the neutrophil p22-phox cytochrome b subunit is associated with a nonfunctional NADPH oxidase and chronic granulomatous disease. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11231-5. PMID:1763037
- ↑ Hossle JP, de Boer M, Seger RA, Roos D. Identification of allele-specific p22-phox mutations in a compound heterozygous patient with chronic granulomatous disease by mismatch PCR and restriction enzyme analysis. Hum Genet. 1994 Apr;93(4):437-42. PMID:8168815
- ↑ Leusen JH, Bolscher BG, Hilarius PM, Weening RS, Kaulfersch W, Seger RA, Roos D, Verhoeven AJ. 156Pro-->Gln substitution in the light chain of cytochrome b558 of the human NADPH oxidase (p22-phox) leads to defective translocation of the cytosolic proteins p47-phox and p67-phox. J Exp Med. 1994 Dec 1;180(6):2329-34. PMID:7964505
- ↑ Rae J, Noack D, Heyworth PG, Ellis BA, Curnutte JT, Cross AR. Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22(phox). Blood. 2000 Aug 1;96(3):1106-12. PMID:10910929
- ↑ Yamada M, Ariga T, Kawamura N, Ohtsu M, Imajoh-Ohmi S, Ohshika E, Tatsuzawa O, Kobayashi K, Sakiyama Y. Genetic studies of three Japanese patients with p22-phox-deficient chronic granulomatous disease: detection of a possible common mutant CYBA allele in Japan and a genotype-phenotype correlation in these patients. Br J Haematol. 2000 Mar;108(3):511-7. PMID:10759707
- ↑ Ishibashi F, Nunoi H, Endo F, Matsuda I, Kanegasaki S. Statistical and mutational analysis of chronic granulomatous disease in Japan with special reference to gp91-phox and p22-phox deficiency. Hum Genet. 2000 May;106(5):473-81. PMID:10914676
- ↑ Teimourian S, Zomorodian E, Badalzadeh M, Pouya A, Kannengiesser C, Mansouri D, Cheraghi T, Parvaneh N. Characterization of six novel mutations in CYBA: the gene causing autosomal recessive chronic granulomatous disease. Br J Haematol. 2008 Jun;141(6):848-51. doi: 10.1111/j.1365-2141.2008.07148.x., Epub 2008 Apr 18. PMID:18422995 doi:10.1111/j.1365-2141.2008.07148.x
- ↑ Ueno N, Takeya R, Miyano K, Kikuchi H, Sumimoto H. The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: its regulation by oxidase organizers and activators. J Biol Chem. 2005 Jun 17;280(24):23328-39. Epub 2005 Apr 11. PMID:15824103 doi:10.1074/jbc.M414548200
- ↑ Liu X, Shi Y, Liu R, Song K, Chen L. Structure of human phagocyte NADPH oxidase in the activated state. Nature. 2024 Mar;627(8002):189-195. PMID:38355798 doi:10.1038/s41586-024-07056-1
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