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===Nuclear pre-mRNA splicing=== |
===Nuclear pre-mRNA splicing=== |
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Galectin-1 and galectin-3 have been found, surprisingly, to associate with nuclear ribonucleoprotein complexes including the spliceosome<ref name="splicing">{{cite journal |author=Haudek. K.C. et al. |title=SR proteins and galectins: what's in a name? |journal=[[Glycobiology]] |volume=20(10) |pages=1199-1207 |year=2010 |doi= 10.1093/glycob/cwq097 |pmcid=PMC2934707}}</ref>. |
Galectin-1 and galectin-3 have been found, surprisingly, to associate with nuclear ribonucleoprotein complexes including the spliceosome<ref name="splicing">{{cite journal |author=Haudek. K.C. et al. |title=SR proteins and galectins: what's in a name? |journal=[[Glycobiology]] |volume=20(10) |pages=1199-1207 |year=2010 |doi= 10.1093/glycob/cwq097 |pmcid=PMC2934707}}</ref>. 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<ref name="splicing 2">{{cite journal |author=Voss, P.G. et al. |title=Dissociation of the carbohydrate-binding and splicing activities of galectin-1 |journal=[[Archives of Biochemistry and Biophysics]] |volume=478 |pages=18-25 |year=2008 |doi= 10.1016/j.abb.2008.07.003 |pmid=18662664}}</ref>. 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. |
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===Knock out mouse studies=== |
===Knock out mouse studies=== |
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Revision as of 18:59, 21 March 2013
GALECTINS
Galectins are a family of proteins defined by their binding specificity for β-galactoside sugars, such as N-acetyllactosamine (Galβ1-3GlcNAc or Galβ1-4GlcNAc), which can be bound to proteins by either N-linked or O-linked glycosylation. 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. They have distinct but overlapping distributions[1] but found primarily in the cytosol, nucleus and extracellular matrix. 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[1].
History
Structure
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. [2]. 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.[3] Galectin-9 has three different isoforms which differ in the length of the linker region.[3]
The galectin carbohydrate recognition domain (CRD) is constructed from beta-sheet of about 135 amino acid. 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.[4]
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 likely 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, 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 [1]. They cannot bind to other sugars such as mannose because this sugar will not fit inside the carbohydrate recognition domain without steric hindrance.
Because of 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[5].
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. [5]
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 signalling that triggers apoptosis[6]. Intracellularly, they can directly regulate proteins that control cell fate.
One essential way galectins regulate apoptosis is to control positive and negative selection of T cells in the thymus. This process prevents the circulation of T cells that recognise self antigen. Both galectin-1 and galectin-9 are secreted by epithelial cells in the thymus and mediate T cell apoptosis. T cell death is also necessary for activated T cells after an immune response. This is also mediated by galectin-1 and galectin-9[6]. Galectin-1 binds many proteins on the T cell surface, but specifically CD7, CD43 and CD45 are involved in apoptosis. Galectin-7 is expressed under the p53 promoter and may have a key role in regulating apoptosis of keratinocytes after DNA damage, such as that caused by UV radiation[6][7]. Galectin-12 expression induces apoptosis of adipocytes[7]. Galectin-3 has been shown to be the only galectin with anti-apoptotic activity. Intracellularly, galectin-3 can associate with Bcl-2 proteins, an antiapoptotic family of proteins, and thus may enhance Bcl-2 binding to the target cell[6]. On the other hand, galectin-3 can also be pro-apoptotic and mediate T cell and neutrophil death[7].
Suppression of T cell receptor activation
Galectin-3 has an essential role in negatively regulating T cell receptor (TCR) activation. Crosslinking of T cell receptors and other glycoproteins by galectin-3 on the membrane of T cells prevents clustering of TCRs and ultimately suppresses activation without the correct stimulus. Experiments in transgenic mice with deficient N-acetylglucosamine transferase V (GnTV) have increased susceptibility to autoimmune diseases[5]. GnTV is the enzyme required to synthesis polylactosamine chains, which are the ligand for galectin-3 on T cell receptors. Thus, 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[2].
Adhesion
Galectins can both promote and inhibit integrin-mediated adhesion. To enhance integrin-mediated adhesion, they can cross link between two glycans on different cells. This brings the cells closer together so integrin binding can occur. They can also hinder adhesion by binding to two glycans on the same cell, which blocks the integrin 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 signalling cascades[8].
Nuclear pre-mRNA splicing
Galectin-1 and galectin-3 have been found, surprisingly, to associate with nuclear ribonucleoprotein complexes including the spliceosome[9]. 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[10]. 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.
Knock out mouse studies
Galectins and disease
Cancer
Galectin-8 has been shown to be downregulated in some cancers[3]. This would be beneficial for the cancer since integrin interactions are decreased and the cancer acquires greater metastatic capabilities.
Chronic inflammation
HIV
Summary
| 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 [7]
Also found in abundance in muscle, neurons and kidney[1] |
Negatively regulate B cell receptor activation
Activate apoptosis in T cells[6] Suppression of Th1 and Th17 immune responses[7] Contributes to nuclear splicing of pre-mRNA[11] |
Can enhance HIV infection
Found upregulated in tumour cells |
| Galectin-2 | Gastrointestinal tract [12] | Binds selectively to β-galactosides of T cells to induce apoptosis[12] | None found |
| Galectin-3 | Wide distribution | Can be pro- or anti-apoptotic (cell dependent)
Regulation of some genes including JNK1 [7] Contributes to nuclear splicing of pre-mRNA[11] 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[7] | Inflammatory bowel disease (IBD)[7] |
| Galectin-7 | Stratified squamous epithelium[7] | Differentiation of keratinocytes
May have a role in apoptosis and cellular repair mediated by p53[7] |
Implications in cancer |
| Galectin-8 | Wide distribution | Binds to integrins of the extracellular matrix[3] | Downregulation in some cancers |
| Galectin-9 | Kidney
Thymus[6] |
Functions as a urate transporter in the kidney [13]
Induces apoptosis of thymocytes and Th1 cells[7][6] 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[7] |
None found |
| Galectin-13 | Placental tissue | Has lysophospholipase activity[14] | None found |
http://www.ncbi.nlm.nih.gov/books/NBK1944/
References
- ^ a b c d
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) - ^ a b 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) - ^ Lobsanov YD, Gitt MA, Leffler H, Barondes SH, Rini JM (1993). "X-ray crystal structure of the human dimeric S-Lac lectin, L-14-II, in complex with lactose at 2.9-A resolution". J. Biol. Chem. 268 (36): 27034–8. PMID 8262940.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b c
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 Hernandez, J.D. and Baum, L.G. (2002). "Ah, sweet mystery of death! Galectins and control of cell fate". Glycobiology. 12: 127–136. PMID 12244068.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b c d e f g h i j k l 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) - ^ Zick, Y.; et al. (2004). "Role of galectin-8 as a modulator of cell adhesion and cell growth". Journal of Glycoconjugates. 19: 517–526. PMID 14758075.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Haudek. K.C.; et al. (2010). "SR proteins and galectins: what's in a name?". Glycobiology. 20(10): 1199–1207. doi:10.1093/glycob/cwq097.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|pmcid=ignored (|pmc=suggested) (help) - ^ Voss, P.G.; et al. (2008). "Dissociation of the carbohydrate-binding and splicing activities of galectin-1". Archives of Biochemistry and Biophysics. 478: 18–25. doi:10.1016/j.abb.2008.07.003. PMID 18662664.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ a b Liu, F.; et al. (2002). "Intracellular functions of galectins". Biochimica et Biophysica Acta. 1572: 263–273. PMID 12223274.
{{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)