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Distinct parts of leukotriene C-4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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2009 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 381, no 4, 518-522 p.Article in journal (Refereed) Published
Abstract [en]

Leukotriene C-4 is a potent inflammatory mediator formed from arachidonic acid and glutathione. 5-Lipoxygenase (5-LO), 5-lipoxygenase activating protein (FLAP) and leukotriene C-4 synthase (LTC4S) participate in its biosynthesis. We report evidence that LTC4S interacts in vitro with both FLAP and 5-LO and that these interactions involve distinct parts of LTC4S. FLAP bound to the N-terminal part/first hydrophobic region of LTC4S. This part did not bind 5-LO which bound to the second hydrophilic loop of LTC4S. Fluorescent FLAP- and LTC4S-fusion proteins co-localized at the nuclear envelope. Furthermore, GFP-FLAP and GFP-LTC4S co-localized with a fluorescent ER marker. In testing HEK293/T or COS-7 cells GFP-5-LO was found mainly in the nuclear matrix. Upon stimulation with calcium ionophore, GFP-5-LO translocated to the nuclear envelope allowing it to interact with FLAP and LTC4S. Direct interaction of 5-LO and LTC4S in ionophore-stimulated (but not un-stimulated) cells was demonstrated by BRET using GFP-5-LO and Rluc-LTC4S.

Place, publisher, year, edition, pages
2009. Vol. 381, no 4, 518-522 p.
Keyword [en]
BRET, Confocal fluorescence microscopy, Eicosanoids, Fusion proteins, GFP, GST pull-down assay, Nuclear envelope
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-17904DOI: 10.1016/j.bbrc.2009.02.074ISI: 000264929400013OAI: oai:DiVA.org:liu-17904DiVA: diva2:212992
Note

Original Publication: Tobias Strid, Jesper Svartz, Niclas Franck, Elisabeth Hallin, Björn Ingelsson, Mats Söderström and Sven Hammarström, Distinct parts of leukotriene C-4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein, 2009, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, (381), 4, 518-522. http://dx.doi.org/10.1016/j.bbrc.2009.02.074 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/

Available from: 2009-04-30 Created: 2009-04-24 Last updated: 2017-12-13Bibliographically approved
In thesis
1. The enzymatic machinery of leukotriene biosynthesis: Studies on ontogenic expression, interactions and function
Open this publication in new window or tab >>The enzymatic machinery of leukotriene biosynthesis: Studies on ontogenic expression, interactions and function
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Leukotrienes (LTs) are biologically active arachidonic acid (AA) derivatives generated by the 5-lipoxygenase (5-LO) pathway. They are produced by myeloid cells. 5-LO converts AA to LTA4 in cooperation with 5-LO activating protein (FLAP). LTA4 is converted to LTB4, by LTA4-hydrolase (LTA4H) or to LTC4 by LTC4-synthase (LTC4S). LTs act on cells through plasma membrane bound G-protein coupled receptors found on leukocytes, smooth muscle and endothelial cells. We report here protein-protein interactions of proteins involved in LTC4 synthesis. 5-LO interacts with cytosolic domains of the integral membrane proteins FLAP and LTC4S at the nuclear envelope, in addition LTC4S interacts with FLAP through its hydrophobic membrane spanning regions. We constructed an LTC4S promoter controlled GFP reporter vector, displaying cell specific expression and sensitivity to agents known to affect LTC4S expression. The vector was used to create transgenic mice expressing GFP as a reporter for LTC4S. Ontogenic mouse expression studies revealed that the complete LT biosynthesis machinery was present at e11.5 primarily in the hematopoietic cells colonizing the liver. Although mature myeloid cells were the main contributors, a substantial amount of FLAP message was also detected in hematopoietic stem and progenitor cells, indicating possible functions for FLAP in hematopoietic regulation. Functional analyses using FLAP knockout mice suggested fine-tuning roles for LTs during differentiation, primarily along the B-lymphocyte differentiation path.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 103 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1287
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-74785 (URN)978-91-7519-987-0 (ISBN)
Public defence
2012-03-09, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
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Supervisors
Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2017-07-07Bibliographically approved

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Strid, TobiasSvartz, JesperFranck, NiclasHallin, ElisabethIngelsson, BjörnSöderström, MatsHammarström, Sven

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