Galectin

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Structure of human galectin-9 in complex with N-acetyllactosamine dimer, clearly showing the two carbohydrate binding sites

Galectins are a class of proteins that bind specifically to

extracellular functions. They have distinct but overlapping distributions[2] but found primarily in the cytosol, nucleus, extracellular matrix or in circulation. Although many galectins must be secreted, they do not have a typical signal peptide required for classical secretion. The mechanism and reason for this non-classical secretion pathway is unknown.[2]

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, consisting 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, -14 and -15. Tandem galectins contain at least two distinct carbohydrate recognition domains (CRD) within one polypeptide, thus are considered intrinsically divalent. The CRDs are linked with a small peptide domain. Tandem galectins include galectin-4, -6, -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 up to a pentameric form.

integrins
and blocks further binding to other cells or the extracellular matrix. When concentrations of galectin-3 are high it forms large complexes that assist in adhesion by bridging between cells or cells and the extracellular matrix. 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. The type of galectin-8 that is expressed is dependent on the tissue.[4] Galectin-9 has three different isoforms which differ in the length of the linker region.[4]

The galectin carbohydrate recognition domain (CRD) is constructed from

amino acids. The two sheets are slightly bent with 6 strands forming the concave side and 5 strands forming the convex side. The concave side forms a groove in which the carbohydrate ligand can bind, and which is long enough to hold about a linear tetrasaccharide.[5]

Ligand binding

Galectins essentially bind to glycans featuring galactose and its derivatives. However, physiologically, they are likely to require lactose or N-acetyllactosamine for significantly strong binding. Generally, the longer the sugar the stronger the interactions. For example, galectin-9 binds to polylactosamine chains with stronger affinity than to an N-acetyllactosamine monomer. This is because more Van der Waals interactions can occur between sugar and binding pocket. Carbohydrate binding is calcium independent, unlike C-type lectins. 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 distinct binding specificities for binding

oligosaccharides
depending on the tissue in which they are expressed and the function that they possess. However, in each case, galactose is essential for binding. Crystallisation experiments of galectins in complex with N-acetyllactosamine show that binding arises due to
steric hindrance. Due to the nature of the binding pocket, galectins can bind terminal sugars or internal sugars within a glycan. This allows bridging between two ligands on the same cell or between two ligands on different cells.[6]

Function

Galectins are a large family with relatively broad specificity. Thus, they have a broad variety of functions including mediation of cell–cell interactions, cell–matrix

knock-out mouse
models. This is because there is substantial overlap for the essential functions. The list of functions for galectins is extensive and it is unlikely they have all been discovered. A handful of the main functions are described below.

Apoptosis

Galectins are distinct in that they can regulate cell death both intracellularly and extracellularly. Extracellularly, they cross link glycans on the outside of cells and transduce signals across the membrane to directly cause cell death or activate downstream signaling that triggers apoptosis.[7] Intracellularly, they can directly regulate proteins that control cell fate. Many galectins have roles in apoptosis:

Suppression of T-cell receptor activation

Galectin-3 has an essential role in negatively regulating

autoimmune diseases.[6]
GnTV is the enzyme required to synthesise polylactosamine chains, which are the ligand for galectin-3 on T cell receptors. This knock-out means galectin-3 cannot prevent auto-activation of TCR so T cells are hypersensitive. Also within the immune system, galectins have been proven to act as chemoattractants to immune cells and activate secretion of inflammatory
cytokines.[3]

Adhesion

Galectins can both promote and inhibit integrin-mediated adhesion. To enhance integrin-mediated adhesion, they cross link between two glycans on different cells. This brings the cells closer together so integrin binding occurs. They can also hinder adhesion by binding to two glycans on the same cell, which blocks the integrin[9] binding site. Galectin-8 is specific for the glycans bound to integrin and has a direct role in adhesion as well as activating integrin-specific signaling cascades.[10]

Nuclear pre-mRNA splicing

Galectin-1 and galectin-3 have been found, surprisingly, to associate with nuclear

ribonucleoprotein complexes including the spliceosome.[11] Studies revealed that galectin-1 and -3 are required splicing factors, since removal of the galectins by affinity chromatography with lactose resulted in loss of splicing activity.[12] It appears that the splicing capability of galectins is independent of their sugar-binding specificities. Site-directed mutagenesis
studies to the carbohydrate recognition domain removes glycan binding but does not prevent association with the spliceosome.

Galectins in control of ESCRT, mTOR, AMPK, and autophagy

Cytoplasmic

LAMTOR1, and RRAGA/RRAGB is known as GALTOR.[13] Galectin-3 and galectin-8 also interact with autophagy receptor-regulator TRIM16 that assembles autophagy initiation machinery on damaged lysosomes,[14] whereas galectin-8 also interacts with the autophagy receptor CALCOCO2 (NDP52) recognizing Salmonella-damaged vacuole.[9]

The functional roles of galectins in cellular response to membrane damage are expanding, e.g. Galectin-3 recruits ESCRTs to damaged lysosomes so that lysosomes can be repaired.[15] This occurs before autophagy is induced to repair endosomes and lysosomes lest they are removed by autophagy.

Galectins and disease

Galectins are abundant, distributed widely around the body and have some distinct functions. It is because of these that they are often implicated in a wide range of diseases such as

allergic reactions
. The most studied and characterised mechanisms are for cancer and HIV, which are described below.

Cancer

The best understood galectin in terms of cancer is galectin-3. Evidence suggests that galectin-3 plays a considerable part in processes linked to

c-myc, which may give it additional tumorigenic properties.[16]
The concentration of galectin-3 is elevated in the circulation of patients with some types of cancer including
endothelial cell walls, such as E-selectin, promoting intravastion into the blood stream.[18] Experiments shows that overexpression of MUC-1 alone is not enough to increase metastatic potential, and in fact it inhibits tumour cell entry into the blood stream. It requires the presence of upregulated galectin-3 in addition to MUC-1 to increase invasive and metastatic properties of the cancer.[18] This is supported by other studies showing that inhibition of galectin-3 in human breast cancer cells lose their malignancy in vitro.[16]
This may provide a clue towards developing therapeutics for cancer, such as galectin-3 inhibitors.

Galectin-8, which increases integrin-mediated adhesion, has been shown to be downregulated in some cancers.[4] This benefits the cancer since integrin interactions with the extracellular matrix prevent metastasis. Lung cancer studies, however, have demonstrated increased adhesion to galectin-8 with increased metastatic potential, which may be mediated by elevated surface expression and activation of integrin α3β1.[17]

Intracellular pathogen invasion

Galectin-8 has been shown to play a specific role in assessing endosomal integrity. After pathogens, such as bacteria or viruses, are engulfed by cells, they typically try to exit the endosome to gain access to nutrients in the cytosol. Galectin-8 specifically binds to glycosylation found within the endosome, and recruits adapter molecule CALCOCO2 which activates antibacterial autophagy.[9] Galectin-3, galectin 8 and galectin-9 have been shown to play additional roles in autophagy both through control of mTOR (galectin-8) and AMPK (galectin-9),[13] and as a factor (galectin-3) in the assembly of the ULK1-Beclin 1-ATG16L1 initiator complex on TRIM16 during endomembrane damage.[14]

HIV

Galectin-1 has been shown to enhance HIV infection due to its galactose binding specificity. HIV preferentially infects

Th1 cells.[8][19] In its normal function, galectin-1 binds to glycans on the CD4 co-receptor of T cells to prevent auto reactivity. When HIV is present, the galectin bridges between the CD4 co-receptor and gp120 ligands, thus facilitating HIV infection of the T cell. Galectin-1 is not essential for HIV infection but assists it by accelerating the binding kinetics between gp120 and CD4. Knowledge of the mechanism between galectin and HIV may provide important therapeutic opportunities. A galectin-1 inhibitor can be used in conjunction with antiretroviral drugs to decrease the infectivity of the HIV and increase the efficacy of the drug.[21] Galectin-3 binds TRIM5α, a cytosolic restriction factor against HIV acting during HIV capsid uncoating, although the precise role of this association remains to be determined.[22] Several galectins bind other TRIMs [22]
some of which are known to contribute to antiviral restriction.

Chagas

N-acetyllactosamine, a galectin-1 ligand, within their N- and O-linked glycans, possibly creating a "Gal-1 resistant glycophenotype."[23]

Table of human galectins

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[8]

Also found in abundance in muscle, neurons and kidney[2]

Negatively regulate B cell receptor activation

Activate apoptosis in T cells[7]

Suppression of Th1 and Th17 immune responses[8]

Contributes to nuclear splicing of pre-mRNA[24]

Can enhance HIV infection

Found upregulated in tumour cells

Galectin-2 Gastrointestinal tract[25] Binds selectively to β-galactosides of T cells to induce apoptosis[25] Risk of myocardial infarction
Galectin-3 Wide distribution Can be pro- or anti-apoptotic (cell dependent)

Regulation of some genes including JNK1[8]

Contributes to nuclear splicing of pre-mRNA[24]

Crosslinking and adhesive properties

In the cytoplasm, helps form the ULK1-Beclin-1-ATG16L1-TRIM16 complex following endomembrane damage[14]

Upregulation occurs in some cancers, including breast cancer, gives increased metastatic potential

Implicated in tuberculosis defense[14]

Galectin-4 Intestine and stomach Binds with high affinity to
lipid rafts suggesting a role in protein delivery to cells[8]
 Inflammatory bowel disease (IBD)[8]
Galectin-7 Stratified squamous epithelium[8] Differentiation of keratinocytes

May have a role in apoptosis and cellular repair mediated by p53.[8]

Implications in cancer Implications in psoriasis
Galectin-8 Wide distribution Binds to integrins of the extracellular matrix.[4] In the cytoplasm, alternatively binds to mTOR or forms the GALTOR complex with SLC38A9, LAMTOR1, and RagA/B[13] Downregulation in some cancers

Implicated in tuberculosis defense

Galectin-9 Kidney

Thymus[7]

Synovial fluid

Macrophages

Functions as a urate transporter in the kidney [26]

Induces apoptosis of thymocytes and Th1 cells[7][8]

Enhances maturation of dendritic cells to secrete inflammatory cytokines. In the cytoplasm, associates upon lysosomal damage with AMPK and activates it[13]

Rheumatoid arthritis

Implicated in tuberculosis defense[13][27]

Galectin-10
 Expressed in
basophils
 Essential role in immune system by suppression of T cell proliferation Found in Charcot–Leyden crystals in asthma
Galectin-12 Adipose tissue Stimulates apoptosis of adipocytes

Involved in adipocyte differentiation[8]

None found
Galectin-13
 Placenta Lysophospholipase Pregnancy complications

References

  1. ^ "Gene group: Galectins (LGALS)". HUGO Gene Nomenclarute Committee.
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External links
This article incorporates text from the public domain Pfam and InterPro: IPR001079
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