Galectin History, Some Stories, and Some Outstanding Questions

Abstract

The proteins now called galectins were discovered about 1975 based on their galactoside-binding activity, in a quest to find proteins that decode complex cell-surface glycans, to take part in cell adhesion. They were defined and named in 1994 based on conserved β-galactoside binding sites found within their characteristic ~130 amino acid (aa) carbohydrate recognition domains (CRDs). However, already at their initial discovery, it was also realized that galectins reside in the cytosol or nucleus for much of their life time, and reach their galactoside ligands only after non-classical secretion that bypasses the Golgi apparatus. Here some of the early studies (mainly before 1994) will be summarized, and exemplified with some galectin stories. The phylogenetic relationships of vertebrate galectins will be summarized as a background. The galectin field has developed rapidly after 1994 in many directions. A few basic outstanding questions will be raised and briefly discussed. What determines galectin binding affinity and specificity for natural glycoconjugate ligands? What is the functional role of galectin fine specificity for carbohydrates? Is there a functional connection between on one hand the cytosolic and nuclear galectin functions and on the other extracellular/intravesicular activities? Are there regulatory loops? A. The OriginsThe first protein now named galectin was reported in 1975 and named electrolectin (1). It was isolated from the electric organ of electric eel, at the time a favored model tissue and source for analysis of nerve cell interactions and receptors because of its many multiplied synapses. The finding of abundant complex carbohydrates at cell surfaces in many tissues including the nervous system, combined with the discoveries of carbohydrates as plant lectin receptors, microbial receptors and blood-group antigens, had stimulated the thought of some glycocode (2-6). Carbohydrates would determine specificities in cell-cell recognition, and there should be proteins binding and recognizing them for this. So, to look for such proteins in the electric organ, Teichberg et al. tested the hemagglutination by tissue extracts, an activity well known for plant lectins, and considered a surrogate marker for possible ability to mediate cell-cell interaction. Having found hemagglutination activity, he tested the ability of various readily available sugars to inhibit it, and found specificity for terminal β-galactose with lactose and thiodigalactoside (TDG) to be most potent inhibitors. Based on this he then used specially treated agarose, with exposed galactose residues, to purify the protein by affinity chromatography. He also found hemagglutination activity with similar profile of inhibitory sugars in many mammalian tissues.Barondes et al., among pioneers in the area, had already found lectins (named discoidins) in cellular slime molds, a model of regulated cell-cell adhesion, using an analogues strategy (7,8).However, they did not at first find the lectin(s) found by Teichberg in animal tissues...

Structure–function studies of galectin‐14, an important effector molecule in embryology

“…Human Gal-14 (UniProt code: Q8TCE9) is a newly identified prototype galectin that shows a 78% sequence identity with Gal-13 [20]. Some galectins with closely related sequences have been given overlapping names, despite their different species expression [21,22]. An eosinophil-specific galectin identified from ovine was also named Gal-14 (UniProt code: W5NT35), even though its primary structure is different from that of human Gal-14.…”

Charcot-Leyden crystal protein/galectin-10 interacts with cationic ribonucleases and is required for eosinophil granulogenesis

“…3,4 CLC protein autocrystallizes to form distinctive hexagonal bipyramidal crystals 5,6 and is the sole protein constituent of both native CLC formed in vivo 7 and CLC prepared from disrupted eosinophils 5,6 and basophils 8 in vitro. CLC is one of the most abundant eosinophil proteins, comprising an estimated 7% to 10% of total cellular protein, 9 and it was previously thought to be an eosinophil lysophospholipase 7,[9][10][11] but has since been reclassified as a member of the galectin superfamily of animal lectins 12 ; it is hereafter referred to as CLC/galectin-10 (Gal-10). However, unlike members of the galectin superfamily, many of which bind lactose and other b-galactoside-containing oligosaccharides and share 12 highly conserved residues that constitute the carbohydrate recognition domain (CRD), [13][14][15][16] CLC/Gal-10 has a putative CRD that contains only 7 of the 12 conserved amino acid residues and does not bind ß-galactosides.…”

Sensing Glycans as Biochemical Messages by Tissue Lectins: The Sugar Code at Work in Vascular Biology

“…This apparent co-evolution with glycans resulting in large lectin numbers strongly argues in favour of the assumed role of lectins as translators for the large panels of glycan-encoded messages. 77 This intra-family divergence is described in further detail for C-type lectins (please see reviews [78][79][80] ), for sialic acid-binding Ig superfamily lectins (siglecs) (please see 81,82 ) and for ga (lactose-binding)lectins [83][84][85][86][87][88] . Notably, in all three cases, species differ in qualitative aspects of gene display and also with respect to gene number and organization, for example, for mammalian galectins 84,89 so that extrapolations from animal models to the clinical situation should always be performed with adequate caution.…”