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PDBsum entry 1hh8
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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S.Grizot,
F.Fieschi,
M.C.Dagher,
E.Pebay-Peyroula.
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Ref.
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J Biol Chem, 2001,
276,
21627-21631.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 1.
Fig. 1. Experimental electron density. The experimental
map at 1.8 Å resolution (contoured at 1  ) is
clearly interpretable and side chains are easily identified.
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Figure 6.
Fig. 6. Environment of Ala-128. The figure shows the
interactions of the extended C terminus (red) with TPR4 (green).
Ala-128 is tightly packed in this environment. Valine at
position 128 (light gray) is superimposed on alanine.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2001,
276,
21627-21631)
copyright 2001.
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