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Abstract
MytiLec is a lectin, isolated from bivalves, with cytotoxic activity against cancer cell lines that express globotriaosyl ceramide, Galα(1,4)Galβ(1,4)Glcα1-Cer, on the cell surface. Functional analysis shows that the protein binds to the disaccharide melibiose, Galα(1,6)Glc, and the trisaccharide globotriose, Galα(1,4)Galβ(1,4)Glc. Recombinant MytiLec expressed in bacteria showed the same haemagglutinating and cytotoxic activity against Burkitt’s lymphoma (Raji) cells as the native form. The crystal structure has been determined to atomic resolution, in the presence and absence of ligands, showing the protein to be a member of the β-trefoil family, but with a mode of ligand binding unique to a small group of related trefoil lectins. Each of the three pseudo-equivalent binding sites within the monomer shows ligand binding, and the protein forms a tight dimer in solution. An engineered monomer mutant lost all cytotoxic activity against Raji cells, but retained some haemagglutination activity, showing that the quaternary structure of the protein is important for its cellular effects.
Highlights
Cells down-regulates cell growth and shows dose-dependent cytotoxic effects that are blocked by the addition of an α-galactoside[1]
The ligand binding mode for MytiLec and the closely related Crenomytilus grayanus lectin (CGL) appears to be novel among β-trefoil lectins
Almost all such proteins have a phenylalanine or tyrosine side-chain lying against the apolar face of the ligand, a feature missing from MytiLec and replaced with the first histidine of the HxDxH motif
Summary
Cells down-regulates cell growth and shows dose-dependent cytotoxic effects that are blocked by the addition of an α-galactoside[1]. The lectin ABL, from the edible mushroom Agaricus bisporus, combines both strong antiproliferative effects on epithelial cancer cells with no apparent cytotoxicity to normal cells[12,13]. It recognises the Thomsen-Friedenreich-antigen (TF-antigen), a well-known disaccharide cell-surface marker for neoplastic cells, consisting of a galactose and N-acetyl-D-galactosamine residue connected by a β(1,3) linkage. The majority of lectins such as ABL and BEL β-trefoil that have been studied for potential medical benefits are specific for β-linked saccharides, so MytiLec is of interest for its unusual ligand specificity and anti-bacterial properties, as well as its demonstrated effects against certain cancer cell lines. The conformation of a complex formed by MytiLec with α-GalNAc was solved, in a different space-group from the apo form
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