Ligand Reduces Galectin-1 Sensitivity to Oxidative Inactivation by Enhancing Dimer Formation

Galectin-1 (Gal-1) regulates leukocyte turnover by inducing the cell surface exposure of phosphatidylserine (PS), a ligand that targets cells for phagocytic removal, in the absence of apoptosis. Gal-1 monomer-dimer equilibrium appears to modulate Gal-1-induced PS exposure, although the mechanism und...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-02, Vol.284 (8), p.4989-4999
Main Authors: Stowell, Sean R., Cho, Moonjae, Feasley, Christa L., Arthur, Connie M., Song, Xuezheng, Colucci, Jennifer K., Karmakar, Sougata, Mehta, Padmaja, Dias-Baruffi, Marcelo, McEver, Rodger P., Cummings, Richard D.
Format: Article
Language:English
Subjects:
Alkylation - drug effects
Amino Acid Substitution
Animals
Calcium - metabolism
Dimerization
Galectin 1 - genetics
Galectin 1 - metabolism
HL-60 Cells
Humans
Iodoacetamide - pharmacology
Leukocytes - metabolism
Ligands
Mice
Mutation, Missense
Oxidation-Reduction - drug effects
Phagocytosis - drug effects
Phagocytosis - physiology
Phosphatidylserines - metabolism
Phosphatidylserines - pharmacology
Signal Transduction - drug effects
Signal Transduction - physiology
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Summary:Galectin-1 (Gal-1) regulates leukocyte turnover by inducing the cell surface exposure of phosphatidylserine (PS), a ligand that targets cells for phagocytic removal, in the absence of apoptosis. Gal-1 monomer-dimer equilibrium appears to modulate Gal-1-induced PS exposure, although the mechanism underlying this regulation remains unclear. Here we show that monomer-dimer equilibrium regulates Gal-1 sensitivity to oxidation. A mutant form of Gal-1, containing C2S and V5D mutations (mGal-1), exhibits impaired dimerization and fails to induce cell surface PS exposure while retaining the ability to recognize carbohydrates and signal Ca2+ flux in leukocytes. mGal-1 also displayed enhanced sensitivity to oxidation, whereas ligand, which partially protected Gal-1 from oxidation, enhanced Gal-1 dimerization. Continual incubation of leukocytes with Gal-1 resulted in gradual oxidative inactivation with concomitant loss of cell surface PS, whereas rapid oxidation prevented mGal-1 from inducing PS exposure. Stabilization of Gal-1 or mGal-1 with iodoacetamide fully protected Gal-1 and mGal-1 from oxidation. Alkylation-induced stabilization allowed Gal-1 to signal sustained PS exposure in leukocytes and mGal-1 to signal both Ca2+ flux and PS exposure. Taken together, these results demonstrate that monomer-dimer equilibrium regulates Gal-1 sensitivity to oxidative inactivation and provides a mechanism whereby ligand partially protects Gal-1 from oxidation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M808925200