| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
The Julius Friedrich Cohnheim-Minerva Center for Phagocyte Research and the Ela Kodesz Institute of Host Defense against Infectious Diseases, Sackler School of Medicine, Tel Aviv University, Israel
1Correspondence: Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: epick{at}post.tau.ac.il
ABSTRACT
Phagocytes generate superoxide (O2.–) by an enzyme complex known as reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Its catalytic component, responsible for the NADPH-driven reduction of oxygen to O2.–, is flavocytochrome b559, located in the membrane and consisting of gp91phox and p22phox subunits. NADPH oxidase activation is initiated by the translocation to the membrane of the cytosolic components p47phox, p67phox, and the GTPase Rac. Cytochrome b559 is converted to an active form by the interaction of gp91phox with p67phox, leading to a conformational change in gp91phox and the induction of electron flow. We designed a new family of NADPH oxidase activators, represented by chimeras comprising various segments of p67phox and Rac1. The prototype chimera p67phox (1–212)-Rac1 (1–192) is a potent activator in a cell-free system, also containing membrane p47phox and an anionic amphiphile. Chimeras behave like bona fide GTPases and can be prenylated, and prenylated (p67phox-Rac1) chimeras activate the oxidase in the absence of p47phox and amphiphile. Experiments involving truncations, mutagenesis, and supplementation with Rac1 demonstrated that the presence of intrachimeric bonds between the p67phox and Rac1 moieties is an absolute requirement for the ability to activate the oxidase. The presence or absence of intrachimeric bonds has a major impact on the conformation of the chimeras, as demonstrated by fluorescence resonance energy transfer, small angle X-ray scattering, and gel filtration. Based on this, a "propagated wave" model of NADPH oxidase activation is proposed in which a conformational change initiated in Rac is propagated to p67phox and from p67phox to gp91phox.
Key Words: superoxide • oxygen radicals • respiratory burst • small GTPases • Rac • GTP/GDP • p67phox • p47phox
This article has been cited by other articles:
|
|
 |
|
  K. A. Gauss, L. K. Nelson-Overton, D. W. Siemsen, Y. Gao, F. R. DeLeo, and M. T. Quinn Role of NF-{kappa}B in transcriptional regulation of the phagocyte NADPH oxidase by tumor necrosis factor-{alpha} J. Leukoc. Biol., September 1, 2007; 82(3): 729 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Berdichevsky, A. Mizrahi, Y. Ugolev, S. Molshanski-Mor, and E. Pick Tripartite Chimeras Comprising Functional Domains Derived from the Cytosolic NADPH Oxidase Components p47phox, p67phox, and Rac1 Elicit Activator-independent Superoxide Production by Phagocyte Membranes: AN ESSENTIAL ROLE FOR ANIONIC MEMBRANE PHOSPHOLIPIDS J. Biol. Chem., July 27, 2007; 282(30): 22122 - 22139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. B. Ammons, D. W. Siemsen, L. K. Nelson-Overton, M. T. Quinn, and K. A. Gauss Binding of Pleomorphic Adenoma Gene-like 2 to the Tumor Necrosis Factor (TNF)-{alpha}-responsive Region of the NCF2 Promoter Regulates p67phox Expression and NADPH Oxidase Activity J. Biol. Chem., June 15, 2007; 282(24): 17941 - 17952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ugolev, S. Molshanski-Mor, C. Weinbaum, and E. Pick Liposomes Comprising Anionic but Not Neutral Phospholipids Cause Dissociation of Rac(1 or 2){middle dot}RhoGDI Complexes and Support Amphiphile-independent NADPH Oxidase Activation by Such Complexes J. Biol. Chem., July 14, 2006; 281(28): 19204 - 19219. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
