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GALECTINS

Galectins are a family of proteins defined by their binding specificity for β-galactoside sugars, such as N-actellactosamine. They are also termed S-type lectins due to their dependency on disulphide bonds for carbohydrate binding. There have been 15 galectins discovered in mammals, encoded by the LGALS genes, which have been numbered in a consecutive manner. Only galectin-1, -2, -3, -4, -7, -8, -9, -10, -12 and -13 have been identified in humans. Galectin-5 and -6 are found in rodents, whereas galectin-11, -14 and -15 are uniquely found in sheep and goats. Members of the galectin family have also been discovered in other mammals, birds, amphibians, fish, nematodes, sponges, and some fungi. Unlike the majority of lectins they are not membrane bound, but soluble proteins with both intra- and extracellular functions.

Structure

The basic cartoon structures of dimeric, tandem and chimeric galectins. Dimeric galectins consist of two of the same subunit that have associated with one another. Tandem galectins have two distinct CRDs linked via a linker peptide domain. Chimera galectins, which consist of only galectin-3 in vertebrates, can exist as a monomer or in a multivalent form. Here it is expressed as a pentamer.

There are three different forms of galectin structure, dimeric, tandem or chimera. Dimeric galectins, also called prototypical galectins, are homodimers of two identical galectin subunits that have associated with one another. The galectins that fall under this category are galectin-1, -2, -5, -7, -10, -11, -13, -14 and -15. Tandem galectins contained at least two distinct carbohydrate recognition domains within one polypeptide. The CRDs are linked with a small peptide domain. Tandem galectins include galectin-4, -5, -8, -9 and -12. The final galectin is galectin-3 which is the only galectin found in the chimera category in vertebrates. Galectin-3 has one CRD and a long non-lectin domain. Galectin-3 can exist in monomeric form or can associate via the non-lectin domain into multivalent complexes . This is concentration dependent. Many isoforms of galectins have been found due to different splicing variants. For example, Galectin-8 has seven different mRNAs encoding for both tandem and dimeric forms. Which type of galectin-8 is expressed is dependent on the tissue. Galectin-9 has three different isoforms which differ in the length of the linker region.

Ligand Binding

The strength of ligand binding is determined by a number of factors. The multivalency of both of ligand and the galectin, the length of the carbohydrate and the mode of presentation of ligand to carbohydrate recognition domain. Different galectins have slightly different binding specificities depending on the tissue in which they are expressed and the function that they possess. For example, galectin-8 has greater affinity to galactose featuring sugars expressed on intregrin of the extracellular matrix. Crystallisation experiments of galectins in complex with β-lactosamine shows that binding arises due to hydrogen bonding interactions from C4 and C6 hydroxyl group of galactose and C3 of N-acetylglucosamine (GlcNAc) to the side chains of amino acids in the protein.

Biosynthesis and distribution

Galectins are not synthesised like other lectins but use the non-classical export route. The mechanism for this is not yet known. Galectins are unique to other lectins because they do not contain any bound sugars of their own. They are soluble proteins that have no signal peptide or membrane binding domain. They are found in the cytosol, nucleus, in the extracellular matrix and extracellularly outside the cell - this is unlike other lectins which are all membrane bound.

Human galectin	Location	Function	Implication in disease
Galectin-1	Secreted by immune cells such as by T helper cells in the thymus or by stromal cells surrounding B cells	Negatively regulate B cell receptor activation. Activate apoptosis in T cells. Suppression of Th1 and Th17 immune responses.	Can enhance HIV infection Found upregulated in tumour cells
Galectin-2	Gastrointestinal tract	Binds selectively to β-galactosides of T cells to induce apoptosis	None found
Galectin-3	Wide distribution	Can be pro- or anti-apoptotic (cell dependent) Regulation of some genes including JNK1 Crosslinking and adhesive properties	Upregulation occurs in some cancers, including breast cancer, gives increased metastatic potential
Galectin-4	Intestine and stomach	Binds with high affinity to lipid rafts suggesting a role in protein delivery	Inflammatory bowel disease (IBD)
Galectin-7	Stratified squamous epithelium	Differentiation of keratinocytes May have a role in the cellular repair programme mediated by p53	Implications in cancer
Galectin-8	Wide distribution	Binds to integrins of the extracellular matrix	Downregulation in some cancers
Galectin-9	Kidney Also secreted by T cells Synovial fluid	Functions as a urate transporter in the kidney Induces apoptosis of thymocytes and Th1 cells Enhances maturation of dendritic cells to secrete inflammatory cytokines	Rheumatoid arthritis
Galectin-10	Expressed in eosinophils and basophils	Essential role in immune system by suppression of T cell proliferation	None found
Galectin-12	Adipose tissue	Stimulates apoptosis of adipocytes Involved in adipocyte differentiation	None found
Galectin-13	Placental tissue	Has lysophospholipase activity	None found

Galectins and disease

Cancer

Galectin-8 has been shown to be downregulated in some cancers. This would be beneficial for the cancer since integrin interactions are decreased and the cancer acquires greater metastatic capabilities.

HIV

http://www.ncbi.nlm.nih.gov/books/NBK1944/