| Structural highlights
8gz3 is a 5 chain structure with sequence from Homo sapiens, Mus musculus and Vicugna pacos. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | 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 oxidase plays an essential role in the first line of host defense against pathogens. It oxidizes intracellular NADPH to reduce extracellular oxygen to produce superoxide anions that participate in pathogen killing. The resting phagocyte oxidase is a heterodimeric complex formed by two transmembrane proteins NOX2 and p22. Despite the physiological importance of this complex, its structure remains elusive. Here, we reported the cryo-EM structure of the functional human NOX2-p22 complex in nanodisc in the resting state. NOX2 shows a canonical 6-TM architecture of NOX and p22 has four transmembrane helices. M3, M4, and M5 of NOX2, and M1 and M4 helices of p22 are involved in the heterodimer formation. Dehydrogenase (DH) domain of NOX2 in the resting state is not optimally docked onto the transmembrane domain, leading to inefficient electron transfer and NADPH binding. Structural analysis suggests that the cytosolic factors might activate the NOX2-p22 complex by stabilizing the DH in a productive docked conformation.
Structure of human phagocyte NADPH oxidase in the resting state.,Liu R, Song K, Wu JX, Geng XP, Zheng L, Gao X, Peng H, Chen L Elife. 2022 Nov 22;11:e83743. doi: 10.7554/eLife.83743. PMID:36413210[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 R, Song K, Wu JX, Geng XP, Zheng L, Gao X, Peng H, Chen L. Structure of human phagocyte NADPH oxidase in the resting state. Elife. 2022 Nov 22;11:e83743. doi: 10.7554/eLife.83743. PMID:36413210 doi:http://dx.doi.org/10.7554/eLife.83743
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