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Originally published In Press as doi:10.1074/jbc.M112393200 on January 16, 2002

J. Biol. Chem., Vol. 277, Issue 15, 13167-13174, April 12, 2002
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Molecular Basis of the Specific Subcellular Localization of the C2-like Domain of 5-Lipoxygenase*

Shilpa KulkarniDagger , Sudipto DasDagger , Colin D. Funk§, Diana Murray, and Wonhwa ChoDagger ||

From the Dagger  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

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.

* 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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