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Abstract
During pregnancy, placental protein-13 (galectin-13) is highly expressed in the placenta and fetal tissue, and less so in maternal serum that is related to pre-eclampsia. To understand galectin-13 function at the molecular level, we solved its crystal structure and discovered that its dimer is stabilized by two disulfide bridges between Cys136 and Cys138 and six hydrogen bonds involving Val135, Val137, and Gln139. Native PAGE and gel filtration demonstrate that this is not a crystallization artifact because dimers also form in solution. Our biochemical studies indicate that galectin-13 ligand binding specificity is different from that of other galectins in that it does not bind β-galactosides. This is partly explained by the presence of Arg53 rather than His53 at the bottom of the carbohydrate binding site in a position that is crucial for interactions with β-galactosides. Mutating Arg53 to histidine does not re-establish normal β-galactoside binding, but rather traps cryoprotectant glycerol molecules within the ligand binding site in crystals of the R53H mutant. Moreover, unlike most other galectins, we also found that GFP-tagged galectin-13 is localized within the nucleus of HeLa and 293 T cells. Overall, galectin-13 appears to be a new type of prototype galectin with distinct properties.
Highlights
Galectins, widely expressed by cells within the animal kingdom[1], all have at least one evolutionarily conserved carbohydrate recognition domain (CRD) that can bind β-galactosides[1,2]
Gal-13 plays a key role in pregnancy and could be valuable at discriminating aneuploid from euploid pregnancies[18] and other obstetrical complications, including intrauterine growth restriction (IUGR), early IUGR, and IUGR associated with pre-eclampsia[19,20]
We found that Gal-13 forms a homodimer structure that is stabilized primarily by the presence of two disulfide bonds, unlike the structures of other prototype galectins
Summary
Widely expressed by cells within the animal kingdom[1], all have at least one evolutionarily conserved carbohydrate recognition domain (CRD) that can bind β-galactosides[1,2]. Even though Gal-13 is predominantly expressed in the placenta ( in the syncytiotrophoblast)[12], it is expressed in the spleen, kidney, and bladder, as well as in liver adenocarcinoma, neurogenic tumors, and malignant melanoma[14]. This lectin can induce apoptosis of activated T cells and regulate immune tolerance between maternal and fetal tissues[13]. The absence of some C-terminal residues in this variant causes the lectin to lose its ability to induce T-cell and macrophage apoptosis[13,27] Women having this variant display a greater incidence of severe pre-eclampsia[13,27]. We report the crystal structure of Gal-13, as well as biochemical and cellular studies on ligand binding specificity and distribution of the lectin in cells
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