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Papers In Press, published online ahead of print September 12, 2000
Dept. Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm SE-171 77
Corresponding Author: Tove.Hammarberg{at}mbb.ki.se
Human 5-lipoxygenase (5LO) is a key enzyme in the conversion of arachidonic acid into leukotrienes and lipoxins, mediators and modulators of inflammation. In this study, we localized a stimulatory Ca2+ binding site into the N-terminal region of the enzyme. Thus, in 45Ca2+ overlay assay, the N-terminal 128 amino acids of recombinant human 5-lipoxygenase (fused to glutathione-S-transferase) bound radioactive calcium to about the same extent as intact 5-lipoxygenase. The GST-fusion protein of the C-terminal part of 5LO (amino acid residues 120-673) showed much weaker binding. Based on the structure of rabbit reticulocyte 15-lipoxygenase, a model of a putative 5-lipoxygenase N-terminal domain was calculated. This model resembled beta-sandwich C2 domains of other Ca2+-binding proteins. Comparison of our model with the C2 domain of cytosolic phospholipase A2 suggested a number of amino acid residues, located in the loops which connect the b-strands, as potential Ca2+ ligands. Indeed, mutations particularly in loop 2 (N43A + D44A + E46A) led to decreased Ca2+-binding, and a requirement for higher Ca2+ concentrations in order to stimulate enzyme activity. Our data indicate that an N-terminal beta-sandwich of 5-lipoxygenase functions as a C2 domain in the calcium regulation of enzyme activity.
J. Biol. Chem, 10.1074/jbc.M006136200
Submitted on July 12, 2000
Revised on September 10, 2000
Accepted on September 12, 2000
The N-terminal domain of 5-lipoxygenase binds calcium and mediates calcium stimulation of enzyme activity
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