1HH8

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

Summary for 1HH8

• Entry DOI: 10.2210/pdb1hh8/pdb
• Related: 1E96
• NMR Information: BMRB: 6399
• Descriptor: NEUTROPHIL CYTOSOL FACTOR 2, CITRATE ANION (3 entities in total)
• Functional Keywords: cell cycle, phagocyte oxidase factor, sh3 domain, tpr repeat cell cycle
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P19878
• Total number of polymer chains: 1
• Total formula weight: 24707.65

Authors

Grizot, S.,Fieschi, F.,Dagher, M.-C.,Pebay-Peyroula, E. (deposition date: 2000-12-21, release date: 2001-06-13, Last modification date: 2024-05-08)

Primary citation

Grizot, S.,Fieschi, F.,Dagher, M.-C.,Pebay-Peyroula, E.
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
J.Biol.Chem., 276:21627-, 2001

PubMed Abstract: 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.

PubMed: 11262407
DOI: 10.1074/JBC.M100893200

Experimental method

X-RAY DIFFRACTION (1.8 Å)