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Originally published In Press as doi:10.1074/jbc.M006136200 on September 12, 2000

J. Biol. Chem., Vol. 275, Issue 49, 38787-38793, December 8, 2000
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The N-terminal Domain of 5-Lipoxygenase Binds Calcium and Mediates Calcium Stimulation of Enzyme Activity*

Tove HammarbergDagger , Patrick ProvostDagger §, Bengt Persson||, and Olof RådmarkDagger **

From the Department of Medical Biochemistry and Biophysics, Divisions of Dagger  Chemistry II and  Chemistry I, and the || Stockholm Bioinformatics Centre, Karolinska Institutet, SE-17177 Stockholm, Sweden

Human 5-lipoxygenase (5-LO) 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 to the N-terminal region of the enzyme. Thus, in a 45Ca2+ overlay assay, the N-terminal 128 amino acids of recombinant human 5-LO (fused to glutathione S-transferase) bound radioactive calcium to about the same extent as intact 5-LO. The glutathione S-transferase fusion protein of the C-terminal part of 5-LO (amino acids 120-673) showed much weaker binding. A model of a putative 5-LO N-terminal domain was calculated based on the structure of rabbit reticulocyte 15-LO. This model resembles 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 acids, located in the loops that connect the beta -strands, as potential Ca2+ ligands. Indeed, mutations particularly in loop 2 (N43A, D44A, and E46A) led to decreased Ca2+ binding and a requirement for higher Ca2+ concentrations to stimulate enzyme activity. Our data indicate that an N-terminal beta -sandwich of 5-LO functions as a C2 domain in the calcium regulation of enzyme activity.

* This work was supported in part by Swedish Medical Research Council Grants 03X-217 and 13X-12564, European Union Grants BMH4-CT96-0229 and Bio4-CT97-2123, the Swedish Foundation for Strategic Research, the Åke Wiberg Foundation, and the Verum Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of fellowships from the Heart and Stroke Foundation of Canada and the Medical Research Council of Canada.

** To whom correspondence should be addressed. Tel.: 46-8-7287624; Fax: 46-8-7360439; E-mail: Olof.Radmark@mbb.ki.se.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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