1wlp

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Solution Structure Of The P22Phox-P47Phox Complex

Structural highlights

1wlp is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The phagocyte NADPH oxidase plays a crucial role in host defense against microbial infections by generating reactive oxygen species. It is a multisubunit enzyme composed of membrane-bound flavocytochrome b558 as well as cytosolic components, including p47phox, which is essential for assembly of the complex. When phagocytes are activated, the cytosolic components of the NADPH oxidase translocate to flavocytochrome b558 due to binding of the tandem Src homology 3 (SH3) domains of p47phox to a proline-rich region in p22phox, a subunit of flavocytochrome b558. Using NMR titration, we first identified the proline-rich region of p22phox that is essential for binding to the tandem SH3 domains of p47phox. We subsequently determined the solution structure of the p47phox tandem SH3 domains complexed with the proline-rich peptide of p22phox using NMR spectroscopy. In contrast to the intertwined dimer reported for the crystal state, the solution structure is a monomer. The central region of the p22phox peptide forms a polyproline type II helix that is sandwiched by the N- and C-terminal SH3 domains, as was observed in the crystal structure, whereas the C-terminal region of the peptide takes on a short alpha-helical conformation that provides an additional binding site with the N-terminal SH3 domain. Thus, the C-terminal alpha-helical region of the p22phox peptide increases the binding affinity for the tandem SH3 domains of p47phox more than 10-fold.

NMR solution structure of the tandem Src homology 3 domains of p47phox complexed with a p22phox-derived proline-rich peptide.,Ogura K, Nobuhisa I, Yuzawa S, Takeya R, Torikai S, Saikawa K, Sumimoto H, Inagaki F J Biol Chem. 2006 Feb 10;281(6):3660-8. Epub 2005 Dec 2. PMID:16326715[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ Ogura K, Nobuhisa I, Yuzawa S, Takeya R, Torikai S, Saikawa K, Sumimoto H, Inagaki F. NMR solution structure of the tandem Src homology 3 domains of p47phox complexed with a p22phox-derived proline-rich peptide. J Biol Chem. 2006 Feb 10;281(6):3660-8. Epub 2005 Dec 2. PMID:16326715 doi:M505193200

Contents


PDB ID 1wlp

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