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J. Biol. Chem., Vol. 277, Issue 15, 13167-13174, April 12, 2002
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From the The activation of 5-lipoxygenase (5-LO) involves
its calcium-dependent translocation to the nuclear
envelope, where it catalyzes the two-step transformation of arachidonic
acid into leukotriene A4, leading to the synthesis of
various leukotrienes. To understand the mechanism by which 5-LO is
specifically targeted to the nuclear envelope, we studied the membrane
binding properties of the amino-terminal domain of 5-LO, which has been
proposed to have a C2 domain-like structure. The model building,
electrostatic potential calculation, and in vitro membrane
binding studies of the isolated C2-like domain of 5-LO and selected
mutants show that this Ca2+-dependent domain
selectively binds zwitterionic phosphatidylcholine, which is conferred
by tryptophan residues (Trp13, Trp75, and
Trp102) located in the putative Ca2+-binding
loops. The spatiotemporal dynamics of the enhanced green fluorescence
protein-tagged C2-like domain of 5-LO and mutants in living cells also
show that the phosphatidylcholine selectivity of the C2-like
domain accounts for the specific targeting of 5-LO to the nuclear
envelope. Together, these results show that the C2-like domain of 5-LO
is a genuine Ca2+-dependent membrane-targeting
domain and that the subcellular localization of the domain is governed
in large part by its membrane binding properties.
Molecular Basis of the Specific Subcellular
Localization of the C2-like Domain of 5-Lipoxygenase*
,,
Department of Chemistry, University of
Illinois, Chicago, Illinois 60607-7061, the ¶ Department of
Microbiology and Immunology, Weill Medical College, Cornell University,
New York, New York 10021, and the § Center for Experimental
Therapeutics and the Department of Pharmacology, University of
Pennsylvania, Philadelphia, Pennsylvania 19104
*
This work was supported by National Institutes of Health
Grants GM52598, GM53987 (to W. C.), and HL58464 (to C. D. F.).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.
Established Investigator of the American Heart Association. To
whom correspondence should be addressed: Dept. of Chemistry (M/C 111),
University of Illinois, 845 West Taylor St., Chicago, IL 60607-7061. Tel.: 312-996-4883; Fax: 312-996-2183; E-mail: wcho@uic.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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