Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A4 production.

Regulation of 5-lipoxygenase (5LO) activity is a key determinant for the biosynthesis of proinflammatory leukotrienes. Coactosin-like protein (CLP) is an F-actin-binding protein that can also bind 5LO. Here, we report that CLP can up-regulate and modulate 5LO activity [formation of 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HPETE)], 5(S)-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HETE), and 5(S)-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid (LTA(4)) ...
in vitro. Three findings are presented. First, CLP up-regulates Ca(2+)-induced 5LO activity, in the absence of phosphatidylcholine (membrane). Apparently, CLP can function as a scaffold for 5LO, similar to membranes. Second, CLP gives a considerable (3-fold) increase in the amount of LTA(4) formed by 5LO, when present together with phosphatidylcholine. Third, CLP increases the ratio of 5-HETE/5-HPETE. These effects require protein interaction by Trp residues in ligand-binding loops of the 5LO beta-sandwich; both binding and stimulatory effects of CLP were abolished for the mutant 5LO-W13/75/102A. In polymorphonuclear leukocytes stimulated with Ca(2+) ionophore, both CLP and 5LO associated with the nucleus, whereas in resting cells, CLP and 5LO were cytosolic. These findings establish CLP as a factor relevant for 5LO product formation. Functioning as a 5LO scaffold, CLP may provide a basis for the formation of 5-HETE in the cytosol of different cell types. Furthermore, in stimulated cells, CLP appears to function in a complex together with 5LO and membranes, increasing the capacity of 5LO for leukotriene biosynthesis.
Mesh Terms:
Arachidonate 5-Lipoxygenase, Calcium, Catalysis, Cell Nucleus, Humans, Ionophores, Kinetics, Leukocytes, Leukotriene A4, Lipid Peroxides, Magnesium, Microfilament Proteins, Mutant Proteins, Peroxidases, Protein Binding, Protein Transport, Time Factors, Tryptophan
Proc. Natl. Acad. Sci. U.S.A.
Date: Aug. 29, 2006
Download Curated Data For This Publication
187690
Switch View:
  • Interactions 1