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Title:
Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A4 production
Authors:
Rakonjac, Marija; Fischer, Lutz; Provost, Patrick; Werz, Oliver; Steinhilber, Dieter; Samuelsson, Bengt; Rådmark, Olof
Publication:
Proceedings of the National Academy of Science, vol. 103, Issue 35, p.13150-13155
Publication Date:
08/2006
Category:
BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Origin:
PNAS
DOI:
10.1073/pnas.0605150103
Bibliographic Code:
2006PNAS..10313150R

Abstract

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 (LTA4) in vitro. Three findings are presented. First, CLP up-regulates Ca2+-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 LTA4 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 β-sandwich; both binding and stimulatory effects of CLP were abolished for the mutant 5LO-W13/75/102A. In polymorphonuclear leukocytes stimulated with Ca2+ 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.

arachidonic acid | eicosanoid | inflammation

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