Membrane fluidity is a key modulator of membrane binding, insertion, and activity of 5-lipoxygenase

    Authors

    A. H. Pande; S. Qin;S. A. Tatulian

    Comments

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    Abbreviated Journal Title

    Biophys. J.

    Keywords

    CYTOSOLIC PHOSPHOLIPASE A(2); LIVER NUCLEAR-MEMBRANE; PROSTAGLANDIN-H; SYNTHASE; N-TERMINAL DOMAIN; SUBCELLULAR-LOCALIZATION; ARACHIDONIC-ACID; C2 DOMAIN; LEUKOTRIENE SYNTHESIS; ALVEOLAR MACROPHAGES; LAURDAN; FLUORESCENCE; Biophysics

    Abstract

    Mammalian 5-lipoxygenase (5-LO) catalyzes conversion of arachidonic acid to leukotrienes, potent mediators of inflammation and allergy. Upon cell stimulation, 5-LO selectively binds to nuclear membranes and becomes activated, yet the mechanism of recruitment of 5-LO to nuclear membranes and the mode of 5-LO-membrane interactions are poorly understood. Here we show that membrane fluidity is an important determinant of membrane binding strength of 5-LO, penetration into the membrane hydrophobic core, and activity of the enzyme. The membrane binding strength and activity of 5-LO increase with the degree of lipid acyl chain cis-unsaturation and reach a plateau with 1-palmitoyl-2-arachidonolyl-sn-glycero-3-phosphocholine ( PAPC). A fraction of tryptophans of 5-LO penetrate into the hydrocarbon region of fluid PAPC membranes, but not into solid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine membranes. Our data lead to a novel concept of membrane binding and activation of 5-LO, suggesting that arachidonic-acid-containing lipids, which are present in nuclear membranes at higher fractions than in other cellular membranes, may facilitate preferential membrane binding and insertion of 5-LO through increased membrane fluidity and may thereby modulate the activity of the enzyme. The data presented in this article and earlier data allow construction of a model for membrane-bound 5-LO, including the angular orientation and membrane insertion of the protein.

    Journal Title

    Biophysical Journal

    Volume

    88

    Issue/Number

    6

    Publication Date

    1-1-2005

    Document Type

    Article

    Language

    English

    First Page

    4084

    Last Page

    4094

    WOS Identifier

    WOS:000229503000036

    ISSN

    0006-3495

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