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J. Biol. Chem., Vol. 278, Issue 12, 10257-10263, March 21, 2003
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From the Department of Internal Medicine, Division of Pulmonary and
Critical Care Medicine, University of Michigan Health System, Ann
Arbor, Michigan 48109-0642
The nuclear import of 5-lipoxygenase modulates
its capacity to produce leukotrienes from arachidonic acid.
However, the molecular determinants of its nuclear import are
unknown. Recently, we used structural and functional criteria to
identify a novel import sequence at Arg518 on human
5-lipoxygenase (Jones, S. M., Luo, M., Healy, A. M., Peters-Golden,
M., and Brock, T. G. (2002) J. Biol. Chem. 277, 38550-38556). However, this analysis also indicated that other import
sequences must exist. Here, we identify two additional sites, at
Arg112 and Lys158, as nuclear import sequences.
Both sites were found to be common to 5-lipoxygenases from different
species but not found on other lipoxygenases. Both sites also appeared
to be a part of structures that were predominantly random loops.
Peptide sequences at these sites were sufficient to direct nuclear
import of green fluorescent protein. Mutation of basic residues in
these sites impaired nuclear import and combinations of mutations at
different sites were additive in effect. Mutations in all three sites
were required to disable nuclear accumulation of 5-lipoxygenase in all
cells. Significantly, mutation in these sites did not inhibit catalytic
function. Taken together, these results indicate that nuclear import of
5-lipoxygenase may reflect the combined functional effects of three
discrete import sequences. Mutation of individual sites can, by
itself, impair nuclear import, which in turn could impact arachidonic acid metabolism.
Identification of Two Novel Nuclear Import Sequences on the
5-Lipoxygenase Protein*
*
This work was supported by National Institutes of Health
Grants R29 AI43574 and R21 AI48141.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.
To whom correspondence should be addressed: Dept. of Internal
Medicine, Division of Pulmonary and Critical Care Medicine, University
of Michigan, Ann Arbor, MI 48109-0642. Tel.: 734-763-9077; Fax:
734-764-4556; E-mail: brocko@umich.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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