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J. Biol. Chem., Vol. 275, Issue 49, 38787-38793, December 8, 2000
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From the Department of Medical Biochemistry and Biophysics,
Divisions of 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
The N-terminal Domain of 5-Lipoxygenase Binds Calcium and
Mediates Calcium Stimulation of Enzyme Activity*
,§,
, and**
Chemistry II and ¶ Chemistry
I, and the Stockholm Bioinformatics Centre, Karolinska
Institutet, SE-17177 Stockholm, Sweden
-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 -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 -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.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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