THE ACTIVE N-TERMINAL REGION OF P67PHOX: STRUCTURE AT 1.8 ANGSTROM RESOLUTION AND BIOCHEMICAL CHARACTERIZATIONS OF THE A128V MUTANT IMPLICATED IN CHRONIC GRANULOMATOUS DISEASE
[NCF2_HUMAN] Defects in NCF2 are a cause of chronic granulomatous disease autosomal recessive cytochrome-b-positive type 2 (CGD2) [MIM:233710]. 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.        
[NCF2_HUMAN] NCF2, NCF1, and a membrane bound cytochrome b558 are required for activation of the latent NADPH oxidase (necessary for superoxide production).
Publication Abstract from PubMed
Upon activation, the NADPH oxidase from neutrophils produces superoxide anions in response to microbial infection. This enzymatic complex is activated by association of its cytosolic factors p67(phox), p47(phox), and the small G protein Rac with a membrane-associated flavocytochrome b(558). Here we report the crystal structure of the active N-terminal fragment of p67(phox) at 1.8 A resolution, as well as functional studies of p67(phox) mutants. This N-terminal region (residues 1-213) consists mainly of four TPR (tetratricopeptide repeat) motifs in which the C terminus folds back into a hydrophobic groove formed by the TPR domain. The structure is very similar to that of the inactive truncated form of p67(phox) bound to the small G protein Rac previously reported, but differs by the presence of a short C-terminal helix (residues 187-193) that might be part of the activation domain. All p67(phox) mutants responsible for Chronic Granulomatous Disease (CGD), a severe defect of NADPH oxidase function, are localized in the N-terminal region. We investigated two CGD mutations, G78E and A128V. Surprisingly, the A128V CGD mutant is able to fully activate the NADPH oxidase in vitro at 25 degrees C. However, this point mutation represents a temperature-sensitive defect in p67(phox) that explains its phenotype at physiological temperature.
The active N-terminal region of p67phox. Structure at 1.8 A resolution and biochemical characterizations of the A128V mutant implicated in chronic granulomatous disease.,Grizot S, Fieschi F, Dagher MC, Pebay-Peyroula E J Biol Chem. 2001 Jun 15;276(24):21627-31. Epub 2001 Mar 21. PMID:11262407
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.