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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 so are considered intrinsically divalent. 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 up to a pentameric form. <ref name="Liu 2010"> |
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 so are considered intrinsically divalent. 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 up to a pentameric form. <ref name="Liu 2010"> |
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{{Cite journal | author=Liu, F.| title=Galectins: Regulators of acute and chronic inflammation | journal=[[Annals of the New York Academy of Sciences]] | volume=1183 | year=2010 | pages=158-182 | doi=10.1111/j.1749-6632.2009.05131.x | pmid=20146714}} |
{{Cite journal | author=Liu, F.| title=Galectins: Regulators of acute and chronic inflammation | journal=[[Annals of the New York Academy of Sciences]] | volume=1183 | year=2010 | pages=158-182 | doi=10.1111/j.1749-6632.2009.05131.x | pmid=20146714}} |
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</ref>. This allows galectin-3 to bridge effectively between different ligands and form adhesive networks. The formation of multimers is concentration dependent. When galactic-3 is at a low concentration, it is monomeric, and is likely to inhibit adhesion since it binds to |
</ref>. This allows galectin-3 to bridge effectively between different ligands and form adhesive networks. The formation of multimers is concentration dependent. When galactic-3 is at a low concentration, it is monomeric, and is likely to inhibit adhesion since it binds to adhesion proteins such as [[integrin]] and blocks binding of other adhesive proteins. When concentrations are high, it forms large complexes that assist in adhesion by bridging between cell-cell or cell-matrix. |
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Many isoforms of galectins have been found due to different [[RNA splicing|splicing]] variants. For example, Galectin-8 has seven different [[messenger RNA|mRNAs]] encoding for both tandem and dimeric forms. Which type of galectin-8 is expressed is dependent on the tissue.<ref name="Cummings book"> |
Many isoforms of galectins have been found due to different [[RNA splicing|splicing]] variants. For example, Galectin-8 has seven different [[messenger RNA|mRNAs]] encoding for both tandem and dimeric forms. Which type of galectin-8 is expressed is dependent on the tissue.<ref name="Cummings book"> |
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{{cite book |last=Varki |first=A |coauthors=Cummings, R.D., Liu, F. |title=Essentials of Glycobiology |edition=2nd |chapter=Chapter 33: Galectins |url=http://www.ncbi.nlm.nih.gov/books/NBK1908/ |year=2009 |publisher=Cold Spring Harbour (NY) |isbn=9780879697709 | pmid=20301264}} |
{{cite book |last=Varki |first=A |coauthors=Cummings, R.D., Liu, F. |title=Essentials of Glycobiology |edition=2nd |chapter=Chapter 33: Galectins |url=http://www.ncbi.nlm.nih.gov/books/NBK1908/ |year=2009 |publisher=Cold Spring Harbour (NY) |isbn=9780879697709 | pmid=20301264}} |
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===Ligand Binding=== |
===Ligand Binding=== |
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Galectins essentially bind to glycans featuring galactose and it's derivatives. However, physiologically, they are likely to require lactose or N-aceyllactosamine 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 interactions can occur between sugar and binding pocket. Carbohydrate binding is calcium independent, unlike C-type lectins. |
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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, but galactose is essential for 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 distinct binding specificities for binding [[oligosaccharides]] depending on the tissue in which they are expressed and the function that they possess, but galactose is essential for binding. |
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Crystallisation experiments of galectins in complex with N-acetyllactosamine shows that binding arises due to [[hydrogen bond|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. |
Crystallisation experiments of galectins in complex with N-acetyllactosamine shows that binding arises due to [[hydrogen bond|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. |
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Revision as of 11:31, 21 March 2013
GALECTINS
Galectins are a family of proteins defined by their binding specificity for β-galactoside sugars, such as N-acetyllactosamine. 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.
History
Structure
Galectins are well conserved across mammals, with 80-90% amino acid sequence identity, but they are less conserved between other classes such as birds.
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 so are considered intrinsically divalent. 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 up to a pentameric form. [1]. This allows galectin-3 to bridge effectively between different ligands and form adhesive networks. The formation of multimers is concentration dependent. When galactic-3 is at a low concentration, it is monomeric, and is likely to inhibit adhesion since it binds to adhesion proteins such as integrin and blocks binding of other adhesive proteins. When concentrations are high, it forms large complexes that assist in adhesion by bridging between cell-cell or cell-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. Which type of galectin-8 is expressed is dependent on the tissue.[2] Galectin-9 has three different isoforms which differ in the length of the linker region.[2]
Ligand Binding
Galectins essentially bind to glycans featuring galactose and it's derivatives. However, physiologically, they are likely to require lactose or N-aceyllactosamine 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 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, but galactose is essential for binding. Crystallisation experiments of galectins in complex with N-acetyllactosamine 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. All galectins bind specifically to galactose containing glycans since the carbohydrate recognition domains are conserved with 20-40% amino acid identity [3]. They cannot bind to other sugars such as mannose because this sugar will not fit inside the carbohydrate recognition domain without steric hindrance.
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 adhesion and transmembrane signalling. Their expression and secretion is well regulated, suggesting they may be expressed at different times during development. [4]
Apoptosis
Suppression of T cell receptor activation
Adhesion
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 [5] | Negatively regulate B cell receptor activation.
Activate apoptosis in T cells. Suppression of Th1 and Th17 immune responses[5]. |
Can enhance HIV infection
Found upregulated in tumour cells |
| Galectin-2 | Gastrointestinal tract [6] | Binds selectively to β-galactosides of T cells to induce apoptosis[6] | None found |
| Galectin-3 | Wide distribution | Can be pro- or anti-apoptotic (cell dependent)
Regulation of some genes including JNK1 [5] 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[5] | Inflammatory bowel disease (IBD)[5] |
| Galectin-7 | Stratified squamous epithelium[5] | Differentiation of keratinocytes
May have a role in the cellular repair programme mediated by p53[5] |
Implications in cancer |
| Galectin-8 | Wide distribution | Binds to integrins of the extracellular matrix[2] | Downregulation in some cancers |
| Galectin-9 | Kidney
Also secreted by T cells Synovial fluid |
Functions as a urate transporter in the kidney [7]
Induces apoptosis of thymocytes and Th1 cells[5] 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[5] |
None found |
| Galectin-13 | Placental tissue | Has lysophospholipase activity[8] | None found |
Galectins and disease
Cancer
Galectin-8 has been shown to be downregulated in some cancers[2]. This would be beneficial for the cancer since integrin interactions are decreased and the cancer acquires greater metastatic capabilities.
Chronic inflammation
HIV
http://www.ncbi.nlm.nih.gov/books/NBK1944/
- ^ Liu, F. (2010). "Galectins: Regulators of acute and chronic inflammation". Annals of the New York Academy of Sciences. 1183: 158–182. doi:10.1111/j.1749-6632.2009.05131.x. PMID 20146714.
- ^ a b c d
Varki, A (2009). "Chapter 33: Galectins". Essentials of Glycobiology (2nd ed.). Cold Spring Harbour (NY). ISBN 9780879697709. PMID 20301264.
{{cite book}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^
Barondes, S.H.; et al. (1994). "Galectins: Structure and function of a large family of animal lectins". The Journal of Biological Chemistry. 269: 20807–10. PMID 8063692.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^
Drickamer, K. (2011). "Chapter 9: Carbohydrate recognition in cell adhesion and signalling". Introduction to Glycobiology (3rd ed.). Oxford University Press. ISBN 978-0-19-956911-3.
{{cite book}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ a b c d e f g h i Yang, R; et al. (2008). "Galectins: Structure, function and therapeutic potential". Expert Reviews in Molecular Medicine. 10: 1–24. doi:10.1017/S1462399408000719. PMID 18549522.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b Sturm, A.; et al. (2004). "Human galectin-2: novel inducer of T cell apoptosis with distinct profile of caspase activation". The Journal of Immunology. 173(6): 3825–37. PMID 15356130.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Graessler, J.; et al. (2000). "Genomic structure of galectin-9 gene. Mutation analysis of a putative human urate channel/transporter". Advances in Experimental Medicine and Biology. 486: 179–183. doi:10.1007/0-306-46843-3_37. PMID 11783481.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Than, N.G.; et al. (2004). "Functional analyses of placental protein 13/galectin-13". European Journal of Biochemistry. 271(6): 1065–78. PMID 15009185.
{{cite journal}}: Explicit use of et al. in:|author=(help)