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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. 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. 5-lipoxygenase cytosolic phospholipase A2 enhanced green fluorescent protein phosphatidylcholine phosphatidylserine 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine surface plasmon resonance 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonic acid human embryonic kidney Leukotrienes are potent lipid mediators of inflammation and allergic responses (1.Funk C.D. Science. 2001; 294: 1871-1875Crossref PubMed Scopus (3070) Google Scholar). 5-Lipoxygenase (5-LO)1 catalyzes the two-step transformation of arachidonic acid into leukotriene A4, which then leads to the synthesis of all leukotrienes (2.Ford-Hutchinson A.W. Gresser M. Young R.N. Annu. Rev. Biochem. 1994; 63: 383-417Crossref PubMed Scopus (417) Google Scholar, 3.Peters-Golden M. Am. J. Respir. Crit. Care Med. 1998; 157: S227-S231Crossref Scopus (73) Google Scholar). Because of its critical role in controlling leukotriene production and the potential to block the production of all leukotrienes by specific inhibitors, 5-LO has been the subject of intense investigation. The cellular regulation of 5-LO activity is regulated by a complex mechanism involving calcium, adenosine triphosphate, and phosphorylation as well as gene transcription (2.Ford-Hutchinson A.W. Gresser M. Young R.N. Annu. Rev. Biochem. 1994; 63: 383-417Crossref PubMed Scopus (417) Google Scholar, 3.Peters-Golden M. Am. J. Respir. Crit. Care Med. 1998; 157: S227-S231Crossref Scopus (73) Google Scholar). The subcellular localization of 5-LO in resting cells varies with the type of cell: it is present primarily in the cytoplasm of neutrophils, monocytes, and peritoneal macrophages, whereas it is predominantly located in the nuclei of rat basophilic leukemia cells and mouse bone marrow-derived mast cells and alveolar macrophages (4.Peters-Golden M. Brock T.G. FEBS Lett. 2001; 487: 323-326Crossref PubMed Scopus (106) Google Scholar). However, cell activation leads to the translocation of 5-LO to the nuclear envelope, where 5-LO-activating protein is located (4.Peters-Golden M. Brock T.G. FEBS Lett. 2001; 487: 323-326Crossref PubMed Scopus (106) Google Scholar). Group IV cytosolic phospholipase A2 (cPLA2), which is critically involved in the production of arachidonic acid, also translocates to the perinuclear region upon activation by calcium (5.Glover S. de Carvalho M.S. Bayburt T. Jonas M. Chi E. Leslie C.C. Gelb M.H. J. Biol. Chem. 1995; 270: 15359-15367Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar). Molecular modeling (6.Hammarberg T. Provost P. Persson B. Radmark O. J. Biol. Chem. 2000; 275: 38787-38793Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar) predicted that the amino-terminal region of 5-LO (∼130 amino acids) might form the structure similar to the C2 domain that has been found in many cellular proteins involved in signaling and membrane trafficking (7.Nalefski E.A. Falke J.J. Protein Sci. 1996; 5: 2375-2390Crossref PubMed Scopus (691) Google Scholar, 8.Rizo J. Sudhof T.C. J. Biol. Chem. 1998; 273: 15879-15882Abstract Full Text Full Text PDF PubMed Scopus (710) Google Scholar, 9.Hurley J.H. Misra S. Annu. Rev. Biophys. Biomol. Struct. 2000; 29: 49-79Crossref PubMed Scopus (226) Google Scholar, 10.Cho W. J. Biol. Chem. 2001; 276: 32407-32410Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar); hereafter, it will be referred to as the 5-LO C2-like domain. C2 domains share a common fold consisting of an eight-strand antiparallel β-sandwich connected by variable loops, which at one end of the domain form the binding sites for multiple Ca2+ ions (7.Nalefski E.A. Falke J.J. Protein Sci. 1996; 5: 2375-2390Crossref PubMed Scopus (691) Google Scholar, 8.Rizo J. Sudhof T.C. J. Biol. Chem. 1998; 273: 15879-15882Abstract Full Text Full Text PDF PubMed Scopus (710) Google Scholar, 9.Hurley J.H. Misra S. Annu. Rev. Biophys. Biomol. Struct. 2000; 29: 49-79Crossref PubMed Scopus (226) Google Scholar, 10.Cho W. J. Biol. Chem. 2001; 276: 32407-32410Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). A prototype C2 domain binds Ca2+ and mediates Ca2+-dependent membrane targeting of proteins. A recent study using the detergent-solubilized inclusion body of the glutathione S-transferase-tagged 5-LO C2-like domain and its mutants indicated that the 5-LO C2-like domain binds calcium ions via several ligands located in the putative calcium-binding loops (6.Hammarberg T. Provost P. Persson B. Radmark O. J. Biol. Chem. 2000; 275: 38787-38793Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Also, a cell study using the green fluorescence protein-tagged 5-LO C2-like domain showed that the 5-LO C2-like domain drives the translocation of 5-LO to the nuclear envelope (11.Chen X.-S. Funk C.D. J. Biol. Chem. 2001; 276: 811-818Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Although these recent reports suggest that the 5-LO C2-like domain might function as a Ca2+-dependent membrane-targeting domain, Ca2+-dependent membrane binding properties of the isolated 5-LO C2-like domain have not been demonstrated. Furthermore, the mechanism by which the 5-LO C2-like domain specifically targets 5-LO to the nuclear envelope is unknown. This study was undertaken to fully characterize the membrane binding properties of the 5-LO C2-like domain and to identify the structural determinants of its specific nuclear envelope targeting. The model building, electrostatic potential calculation, and in vitromembrane binding studies of the isolated 5-LO C2-like domain and selected mutants establish that the 5-LO C2-like domain is a genuine Ca2+-dependent membrane-targeting domain with unique selectivity for zwitterionic phosphatidylcholine (PC), which is conferred by tryptophan residues located in the putative Ca2+-binding loops. The spatiotemporal dynamics of the enhanced green fluorescence protein (EGFP)-tagged 5-LO C2-like domain and mutants in living cells also indicate that the PC selectivity of the domain accounts for the specific targeting of 5-LO to the nuclear envelope. 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine (POPS), and N-5-dimethylaminonaphthalene-1-sulfonyl-1-palmitoyl-2-oleyl-sn-glycero-3-phosphoethanolamine were purchased from Avanti Polar Lipids, Inc. (Alabaster, AL) and used without further purification. Phospholipid concentrations were determined by phosphate analysis. The Liposofast microextruder and 100-nm polycarbonate filters were from Avestin, Inc. (Ottawa, Ontario, Canada). Fatty acid-free bovine serum albumin was from Bayer Inc. (Kankakee, IL). 35S-Labeled adenosine triphosphate and45CaCl2 were from Amersham Biosciences, Inc. Triton X-100 was from Pierce. Restriction endonucleases and enzymes for molecular biology were obtained from New England Biolabs Inc. (Beverly, MA), and Pfu polymerase was from Stratagene (La Jolla, CA). The Pioneer L1 sensor chip was from BIAcore AB (Piscataway, NJ). Ionomycin was from Calbiochem. ZeocinTM and pronasterone A were from Invitrogen (Carlsbad, CA). The C2 domain of cPLA2 was prepared as described previously (12.Bittova L. Sumandea M. W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the of the 5-LO C2-like domain was into the with an amino-terminal was by the was used as the for protein of with was with of at were at the at and then protein was with IL). at cells were by at for at were in of Triton and The cell was with of of by of the was the inclusion body was obtained by at for at The was in the and with in of at The protein was using a acid to the The protein were and by the and and The protein was and at The protein was in for analysis. 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Biol. 2000; PubMed Scopus Google we selected the for E. Struct. Biol. PubMed Scopus Google Scholar) and an from and Struct. Biol. 1998; 5: PubMed Scopus Google Scholar, M. J. B. J. Biol. 294: PubMed Scopus Google Scholar) as and structural for the 5-LO C2-like domain. for the 5-LO C2-like domain were with the J. Biol. PubMed Scopus Google and the model the as structural was used in the electrostatic potential the modeling the 5-LO and C2-like domain and as by in the S. Sci. S. PubMed Scopus Google Scholar). The structural and model were using the PubMed Scopus Google which to well into its structural from of the Protein The model that were to the structural an that the model is for the type of A model using as a similar The calcium ions were into the model using structure of the model and the C2-like domain structure with calcium ions The electrostatic properties of the 5-LO C2-like domain model were and in the B. PubMed Scopus Google Scholar). and the and the and electrostatic in various C2 and C2-like domains with we found potential structural for the 5-LO C2-like E. Struct. Biol. PubMed Scopus Google Scholar) and the C2-like domain of Struct. Biol. 1998; 5: PubMed Scopus Google Scholar, M. J. B. J. Biol. 294: PubMed Scopus Google Scholar). The is this domain binds calcium and a the C2-like domains of and 5-LO that 5-LO has of the residues The as by was by a Scholar) multiple of all C2-like domains and then the for the C2-like domain of and the 5-LO C2-like domain the model for the 5-LO C2-like domain using the C2-like domain of as a structural Although this model structure has potential calcium-binding calcium ions are in the model one have calcium to the of a in of in the C2-like domain of This is with the that 5-LO binds Ca2+ ions T. Radmark O. PubMed Scopus Google Scholar). The results of the electrostatic are of which sites are to be model of the 5-LO C2-like domain. The modeling for the 5-LO C2-like domain was using an from as a structural The model is as a with the residues and putative residues as green and calcium has been that 5-LO binds with an of in the and of PC T. Radmark O. PubMed Scopus Google Scholar). However, the calcium binding of the isolated 5-LO C2-like domain has been using a detergent-solubilized inclusion body of the glutathione S-transferase-tagged 5-LO C2-like domain (6.Hammarberg T. Provost P. Persson B. Radmark O. J. Biol. Chem. 2000; 275: 38787-38793Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). the calcium of the isolated 5-LO C2-like domain by The 5-LO C2-like domain was in E. as an inclusion which was and to in the isolated 5-LO C2-like domain Ca2+ ions in the and of Although it has been that calcium ions to C2 domains in a E.A. Falke J.J. PubMed Scopus Google Scholar, E.A. M. Falke J.J. 2001; PubMed Scopus Google the calcium binding in were to a to that are to that of 5-LO T. Radmark O. PubMed Scopus Google Scholar). This that the calcium of 5-LO from the 5-LO C2-like domain. To establish that the 5-LO C2-like domain is a genuine calcium-dependent membrane-targeting domain, we the membrane binding properties of the isolated 5-LO C2-like domain by analysis. of membrane and for proteins W. 2001; PubMed Scopus Google W. L. Biochem. 2001; PubMed Scopus Google Scholar). the binding of the 5-LO C2-like domain to with at in the 5-LO C2-like domain of for zwitterionic PC for and this the 5-LO C2-like domain is similar to the cPLA2 C2 domain, which also has unique PC selectivity W. J. Biol. Chem. 2001; 276: 32407-32410Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, E.A. T. W. J. Falke J.J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). This is also with the that 5-LO binds PC and activity in the of PC in the of M. M. T. M. Biophys. 1994; PubMed Scopus Google Scholar). then the binding of the 5-LO C2-like domain to PC as a function of the of Ca2+ binding was with protein to that the 5-LO C2-like domain has for this The in calcium from to in a in its Ca2+-dependent membrane binding in the in Ca2+ and to a binding of the 5-LO C2-like domain and C2-like the from to in a the from to To further characterize the membrane binding properties of the 5-LO C2-like domain, we its with The has been to be a for the membrane of proteins W. L. Biochem. 2001; PubMed Scopus Google Scholar, Chem. Scopus Google Scholar). the of the 5-LO C2-like domain into the in the and of Ca2+ in with the cPLA2 C2 domain. previously showed that Ca2+ the of the cPLA2 C2 domain by and residues in the Ca2+-binding loops (12.Bittova L. Sumandea M. W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). in Ca2+ also enhanced the of the 5-LO C2-like domain, not as as with the cPLA2 C2 domain. This that a role of Ca2+ in the membrane binding of the 5-LO C2-like domain is to a in the Ca2+-binding loops to residues for membrane then the of the 5-LO C2-like domain with with with the PC selectivity in the binding the 5-LO C2-like domain into in the of of the 5-LO C2-like domain into of 5-LO C2-like domain was into of the and the at a was then as a function of The model structure of the 5-LO C2-like domain the of tryptophan residues (Trp13, Trp75, and Trp102) in the Ca2+-binding loops. recent study the cPLA2 C2 domain showed that residues in the Ca2+-binding loops are involved in its PC J. S. and W. for the tryptophan residues to and the membrane of mutants by and to not these residues are involved in the PC selectivity of the 5-LO C2-like domain. in all the PC of the domain, to and and for PC in of and the and to a whereas for the previously that the of tryptophan residues and in are in in W. Biochem. J. 2001; PubMed Scopus Google Scholar). indicate that the residues in are involved in the membrane binding of the 5-LO C2-like domain, a role of the membrane and the membrane the of the residues with a in a mutants and showed for The PC selectivity in of the of for PC to from to for the whereas it was for the 5-LO C2-like domain. it is that the residues are involved in the PC selectivity of the 5-LO C2-like domain. then the of the in and into the whereas with the 5-LO C2-like showed a in indicate that the residues and in are involved in into the the 5-LO C2-like domain, which the to the the mutants not have PC selectivity in not further the that the residues are involved in specific PC and described indicated that of surface residues with PC a role in the membrane binding of the 5-LO C2-like domain. To for the of this we the electrostatic of and 5-LO C2-like the domain has a of and is in the of This potential a for the domain to to to the with the domain to the membrane binding to electrostatic the potential of the domain and lipid also the that the potential in the Ca2+-binding region is by the Ca2+ ions that the with the domain to the membrane surface is the potential the region Trp75, and is This residues to into the membrane and of the electrostatic described the is to be for PC for is the with the cPLA2 C2 domain (12.Bittova L. Sumandea M. W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the Ca2+ binding also the in these to for membrane the 5-LO C2-like domain is in the it is that will be from and this to the PC selectivity of the domain. To the role of the 5-LO C2-like domain in the subcellular localization of 5-LO and also to the of in vitro we the 5-LO C2-like domain and mutants with into cells and spatiotemporal dynamics by in the 5-LO C2-like domain was in the cytoplasm and the in the resting the cells were by the Ca2+ the 5-LO C2-like domain to the nuclear the translocation was protein in the to be to the of the nuclear envelope by the has been that is in the of cells M.S. New Biol. PubMed Scopus Google Scholar, Biophys. PubMed Scopus (710) Google whereas PC is present in the nuclear J. 2000; Full Text Full Text PDF PubMed Google Scholar). and have also that C2 domains of protein and phospholipase B. S. W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) to the whereas the cPLA2 C2 domain translocates to the perinuclear region O. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Leslie C.C. J. Biol. PubMed Scopus Google Scholar). it that the subcellular localization of the 5-LO C2-like domain is with its PC This is by the subcellular localization of mutants and which have PC to the 5-LO C2-like domain, these mutants to the membrane and nuclear envelope in to Ca2+ Together, these cell show that the 5-LO C2-like domain is a genuine Ca2+-dependent membrane-targeting domain, the subcellular localization of which is governed in large part by its membrane binding properties. This the in vitro and cell studies the isolated C2-like domain of and electrostatic potential calculation, and cell translocation studies show that the 5-LO C2-like domain is a genuine Ca2+-dependent membrane-targeting domain that binds calcium ions and has PC this the 5-LO C2-like domain is similar to the cPLA2 C2 domain. The cPLA2 C2 domain binds with an of E.A. Falke J.J. PubMed Scopus Google Scholar, E.A. M. Falke J.J. 2001; PubMed Scopus Google Scholar). modeling the of Ca2+-binding sites in the 5-LO C2-like domain. was previously that 5-LO binds Ca2+ ions with an of in the and of PC T. Radmark O. PubMed Scopus Google Scholar). show that the isolated 5-LO C2-like domain also binds Ca2+ ions with similar Furthermore, results indicate that similar in the membrane binding of the cPLA2 C2 and 5-LO C2-like have been proposed for the C2 Ca2+ ions J.H. Misra S. Annu. Rev. Biophys. Biomol. Struct. 2000; 29: 49-79Crossref PubMed Scopus (226) Google W. J. Biol. Chem. 2001; 276: 32407-32410Abstract Full Text Full Text PDF PubMed Scopus (192) Google electrostatic potential of a lipid and of the cPLA2 C2 domain, Ca2+ has been to the of and residues in the Ca2+-binding loops, leading to membrane and (12.Bittova L. Sumandea M. W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Gelb M.H. Sci. S. PubMed Scopus Google Scholar, E.A. Falke J.J. 1998; PubMed Scopus Google Scholar). The electrostatic potential also that Ca2+ might the binding of the cPLA2 C2 domain to the PC membrane by which the with the and domain to the PC membrane surface B. Full Text Full Text PDF PubMed Scopus Google Scholar). The present study that Ca2+ ions the role for the 5-LO C2-like domain. Because the 5-LO C2-like domain is in the of the by the Ca2+ ions is for the with the domain to the membrane indicate that the of the to for membrane A the C2 domains is that Ca2+ is for the of the cPLA2 C2 domain, whereas the 5-LO C2-like domain has in the of Ca2+ it that and residues in the 5-LO C2-like domain are in a in the and that the calcium binding a study showed that residues and the membrane whereas and residues membrane membrane W. 2001; PubMed Scopus Google Scholar). the of the cPLA2 C2 domain, calcium as it primarily the membrane of residues and in the calcium-binding loops W. Biochem. J. 2001; PubMed Scopus Google Scholar). calcium it the membrane binding of A of Ca2+-dependent C2 domains to zwitterionic calcium electrostatic potential the surface B. S. W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Full Text Full Text PDF PubMed Scopus Google calcium to an S. J. PubMed Scopus Google Scholar). To the and 5-LO C2-like domains are the C2 domains with PC recent study showed that and located in the Ca2+-binding loops are critically involved in the PC selectivity of the A recent electrostatic potential also showed that the PC selectivity of the cPLA2 C2 domain be by a electrostatic of cPLA2 C2 domain at the surface of at the surface of PC B. Full Text Full Text PDF PubMed Scopus Google Scholar). results indicate that the PC selectivity of the 5-LO C2-like domain from similar The of PC selectivity by the of Trp75, to with the PC is also that the PC selectivity from the that it is for residues to into PC into Because the zwitterionic PC are and not by it is that the of the residues into the PC membrane is that into an with the cPLA2 C2 domain, the 5-LO C2-like domain is in the and it be from the membrane this also to the PC selectivity of the domain. the results described show the cPLA2 C2 and 5-LO C2-like that the 5-LO C2-like domain binds to the membrane in an to the membrane of as proposed for the cPLA2 C2 domain W. J. Biol. Chem. 2001; 276: 32407-32410Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, L. Sumandea M. W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Although this model structure the of and the putative surface that might also an role in membrane binding of the domain. studies are in to the of these residues to the of membrane binding of the 5-LO C2-like domain. The by which 5-LO is regulated in the cell This study that Ca2+-dependent membrane binding properties of the 5-LO C2-like domain selectivity in its subcellular localization Although the lipid of cellular of cells has not been determined it is from the lipid of subcellular that the of cells are in and that the perinuclear the nuclear envelope, PC and M.S. New Biol. PubMed Scopus Google Scholar, Biophys. PubMed Scopus (710) Google Scholar, J. 2000; Full Text Full Text PDF PubMed Google Scholar). to Ca2+ the 5-LO C2-like domain, with PC translocates to the nuclear envelope. and which have PC are to the membrane and the nuclear envelope, the that the specific targeting of the 5-LO C2-like domain to the nuclear envelope is to its PC this the 5-LO C2-like domain as a genuine Ca2+-dependent membrane-targeting that has membrane binding properties and that a role in the subcellular localization of this study the for further of the complex mechanism of membrane targeting and activation of 5-LO, which calcium, protein and for with and for the C2-like domain
Kulkarni et al. (Mon,) studied this question.
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