Biology:Concanavalin A

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Short description: Lectin (carbohydrate-binding protein) originally extracted from the jack-bean
Concanavalin A
3CNA Concanavalin A.png
Crystallographic structure of a tetramer of jack bean concanavalin A (the monomers are colored cyan, green, red, and magenta respectively). Calcium (gold) and manganese cations (grey) are depicted as spheres.[1]
Identifiers
OrganismCanavalia virosa (jackbean)
SymbolConA
PDB3CNA (ECOD)
UniProtP81461

Concanavalin A (ConA) is a lectin (carbohydrate-binding protein) originally extracted from the jack-bean (Canavalia ensiformis). It is a member of the legume lectin family. It binds specifically to certain structures found in various sugars, glycoproteins, and glycolipids, mainly internal and nonreducing terminal α-D-mannosyl and α-D-glucosyl groups.[2][3] Its physiological function in plants, however, is still unknown. ConA is a plant mitogen, and is known for its ability to stimulate mouse T-cell subsets giving rise to four functionally distinct T cell populations, including precursors to regulatory T cells;[4] a subset of human suppressor T-cells is also sensitive to ConA.[4] ConA was the first lectin to be available on a commercial basis, and is widely used in biology and biochemistry to characterize glycoproteins and other sugar-containing entities on the surface of various cells.[5] It is also used to purify glycosylated macromolecules in lectin affinity chromatography,[6] as well as to study immune regulation by various immune cells.[4]

Structure and properties

Like most lectins, ConA is a homotetramer: each sub-unit (26.5kDa, 235 amino-acids, heavily glycated) binds a metallic atom (usually Mn2+ and a Ca2+). It has the D2 symmetry.[1] Its tertiary structure has been elucidated,[7] as have the molecular basis of its interactions with metals as well as its affinity for the sugars mannose and glucose[8] are well known.

ConA binds specifically α-D-mannosyl and α-D-glucosyl residues (two hexoses differing only in the alcohol on carbon 2) in terminal position of ramified structures from B-Glycans (rich in α-mannose, or hybrid and bi-antennary glycan complexes). It has 4 binding sites, corresponding to the 4 sub-units.[3] The molecular weight is 104-112kDa and the isoelectric point (pI) is in the range of 4.5-5.5.

ConA can also initiate cell division (mitogenesis), primarily acting on T-lymphocytes, by stimulating their energy metabolism within seconds of exposure.[9]


Maturation process

ConA and its variants (found in closely related plants) are the only proteins known to undergo a post-translational sequence arrangement known as Circular permutation in proteins whereby the N-terminal half of the conA precursor is swapped to become the C-terminal half in the mature form; all other known circular permutations occur at the genetic level.[10][11] ConA circular permutation is carried out by jack bean asparaginyl endopeptidase,[12] a versatile enzyme capable of cleaving and ligating peptide substrates at a single active site.[13] To convert conA to the mature form, jack bean asparaginyl endopeptidase cleaves the precursor of conA in the middle and ligates the two original termini.

Biological activity

Concanavalin A interacts with diverse receptors containing mannose carbohydrates, notably rhodopsin, blood group markers, insulin-receptor[14] the Immunoglobulins and the carcino-embryonary antigen (CEA). It also interacts with lipoproteins.[15]

ConA strongly agglutinates erythrocytes irrespective of blood-group, and various cancerous cells.[16][17][18] It was demonstrated that transformed cells and trypsin-treated normal cells do not agglutinate at 4 °C, thereby suggesting that there is a temperature-sensitive step involved in ConA-mediated agglutination.[19][20]

ConA-mediated agglutination of other cell types has been reported, including muscle cells ,[21] B-lymphocytes (through surface Immunoglobulins),[22] fibroblasts,[23] rat thymocytes,[24] human fetal (but not adult) intestinal epithelial cells,[25] and adipocytes.[26]

ConA is a lymphocyte mitogen. Similar to phytohemagglutinin (PHA), it is a selective T cell mitogen relative to its effects on B cells. PHA and ConA bind and cross-link components of the T cell receptor, and their ability to activate T cells is dependent on expression of the T cell receptor.[27][28]

ConA interacts with the surface mannose residues of many microbes, including the bacteria E. coli,[29] and Bacillus subtilis[30] and the protist Dictyostelium discoideum.[31]

It has also been shown as a stimulator of several matrix metalloproteinases (MMPs).[32]

ConA has proven useful in applications requiring solid-phase immobilization of glycoenzymes, especially those that have proved difficult to immobilize by traditional covalent coupling. Using ConA-couple matrices, such enzymes may be immobilized in high quantities without a concurrent loss of activity and/or stability. Such noncovalent ConA-glycoenzyme couplings may be relatively easily reversed by competition with sugars or at acidic pH. If necessary for certain applications, these couplings can be converted to covalent bindings by chemical manipulation.[33]

A report from Taiwan (2009) demonstrated potent therapeutic effect of ConA against experimental hepatoma (liver cancer); in the study by Lei and Chang,[34] ConA was found to be sequestered more by hepatic tumor cells, in preference to surrounding normal hepatocytes. Internalization of ConA occurs preferentially to the mitochondria after binding to cell membrane glycoproteins, which triggers an autophagic cell death. ConA was found to partially inhibit tumor nodule growth independent of its lymphocyte activation; the eradication of the tumor in the murine in-situ hepatoma model in this study was additionally attributed to the mitogenic/lymphoproliferative action of ConA that may have activated a CD8+ T-cell-mediated, as well as NK- and NK-T cell-mediated, immune response in the liver.[34]

ConA intravitreal injection can be used in the modeling of proliferative vitreoretinopathy in rats.[35][36]

References

  1. ↑ 1.0 1.1 PDB: 3CNA​; "Structure of concanavalin A at 2.4-A resolution". Biochemistry 11 (26): 4910–4919. December 1972. doi:10.1021/bi00776a006. PMID 4638345. 
  2. ↑ Goldstein, Irwin J.; Poretz, Ronald D. (2012). "Isolation, physicochemical characterization, and carbohydrate-binding specificity of lectins". in Liener, Irvin E.; Sharon, Nathan; Goldstein, Irwin J.. The Lectins Properties, Functions and Applications in Biology and Medicine. Elsevier. pp. 33–247. ISBN 978-0-323-14444-5. https://books.google.com/books?id=uiwd4XqOLbMC&pg=PA33. 
  3. ↑ 3.0 3.1 "The Molecular Weights of Urease, Canavalin, Concanavalin a and Concanavalin B". Science 87 (2261): 395–396. April 1938. doi:10.1126/science.87.2261.395. PMID 17746464. Bibcode: 1938Sci....87..395S. 
  4. ↑ 4.0 4.1 4.2 "The use of concanavalin A to study the immunoregulation of human T cells". Clinical and Experimental Immunology 46 (2): 237–249. November 1981. PMID 6461456. 
  5. ↑ "Ultrastructural visualization of surface carbohydrate structures on mycoplasma membranes by concanavalin A". Journal of Bacteriology 124 (3): 1598–1600. December 1975. doi:10.1128/JB.124.3.1598-1600.1975. PMID 1104592. 
  6. ↑ GE Healthcare Life Sciences, Immobilized lectin [full citation needed]
  7. ↑ "Non-glycosylated recombinant pro-concanavalin A is active without polypeptide cleavage". The EMBO Journal 11 (4): 1303–1307. April 1992. doi:10.1002/j.1460-2075.1992.tb05174.x. PMID 1563347. 
  8. ↑ "Legume lectin structure". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 1383 (1): 9–36. March 1998. doi:10.1016/S0167-4838(97)00182-9. PMID 9546043. 
  9. ↑ "Effects of the mitogen concanavalin A on pathways of thymocyte energy metabolism". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1412 (2): 129–138. June 1999. doi:10.1016/S0005-2728(99)00058-4. PMID 10393256. 
  10. ↑ "Polypeptide ligation occurs during post-translational modification of concanavalin A". Nature 313 (5997): 64–67. 1985. doi:10.1038/313064a0. PMID 3965973. Bibcode: 1985Natur.313...64C. 
  11. ↑ "Protein carpentry". Current Biology 1 (2): 71–73. April 1991. doi:10.1016/0960-9822(91)90280-a. PMID 15336168. 
  12. ↑ "Structural and biochemical analyses of concanavalin A circular permutation by jack bean asparaginyl endopeptidase". The Plant Cell 33 (8): 2794–2811. August 2021. doi:10.1093/plcell/koab130. PMID 34235541. 
  13. ↑ "Plant asparaginyl endopeptidases and their structural determinants of function". Biochemical Society Transactions 49 (2): 965–976. April 2021. doi:10.1042/BST20200908. PMID 33666219. 
  14. ↑ "Insulin-like activity of concanavalin A and wheat germ agglutinin--direct interactions with insulin receptors". Proceedings of the National Academy of Sciences of the United States of America 70 (2): 485–489. February 1973. doi:10.1073/pnas.70.2.485. PMID 4510292. Bibcode: 1973PNAS...70..485C. 
  15. ↑ "Interaction of human plasma low density lipoprotein with concanavalin A and with ricin". The Journal of Biological Chemistry 250 (22): 8614–8617. November 1975. doi:10.1016/S0021-9258(19)40714-X. PMID 171260. [yes|permanent dead link|dead link}}]
  16. ↑ "Agglutination reactions of spontaneous canine tumour cells, induced by concanavalin A, demonstrated by an isotopic assay". International Journal of Cancer 18 (5): 687–696. November 1976. doi:10.1002/ijc.2910180518. PMID 992901. 
  17. ↑ "Increased agglutinability of bladder cells by concanavalin A after administration of carcinogens". Cancer Research 40 (6): 2006–2009. June 1980. PMID 7371036. 
  18. ↑ "Concanavalin A agglutination of cells from primary hepatocellular carcinomas and hepatic nodules induced by N-2-fluorenylacetamide". Cancer Research 35 (10): 2879–2883. October 1975. PMID 168971. 
  19. ↑ "A specific metabolic activity on the surface membrane in malignant cell-transformation". Proceedings of the National Academy of Sciences of the United States of America 68 (11): 2748–2751. November 1971. doi:10.1073/pnas.68.11.2748. PMID 4330939. Bibcode: 1971PNAS...68.2748I. 
  20. ↑ "Quantitation of N-acetyl-D-galactosamine-like sites on the surface membrane of normal and transformed mammalian cells". Biochimica et Biophysica Acta (BBA) - Biomembranes 249 (2): 564–568. December 1971. doi:10.1016/0005-2736(71)90132-5. PMID 4332414. 
  21. ↑ "Evidence that a membrane bound lectin mediates fusion of L6 myoblasts". Biochemical and Biophysical Research Communications 67 (3): 972–978. December 1975. doi:10.1016/0006-291X(75)90770-6. PMID 1201086. 
  22. ↑ "Concanavalin A receptors, immunoglobulins, and theta antigen of the lymphocyte surface. Interactions with concanavalin A and with Cytoplasmic structures". The Journal of Cell Biology 65 (1): 123–146. April 1975. doi:10.1083/jcb.65.1.123. PMID 1092699. 
  23. ↑ "The relationship of concanavalin A binding to lectin-initiated cell agglutination". The Journal of Cell Biology 59 (1): 134–142. October 1973. doi:10.1083/jcb.59.1.134. PMID 4201706. 
  24. ↑ "Concanavalin-A-mediated thymocyte agglutination: a model for a quantitative study of cell adhesion". Journal of Cell Science 56: 21–48. August 1982. doi:10.1242/jcs.56.1.21. PMID 7166565. 
  25. ↑ "Concanavalin A agglutination of intestinal cells from the human fetus". Science 177 (4048): 525–526. August 1972. doi:10.1126/science.177.4048.525. PMID 5050484. Bibcode: 1972Sci...177..525W. 
  26. ↑ "Interaction of wheat germ agglutinin and concanavalin A with isolated fat cells". Biochemistry 12 (7): 1312–1323. March 1973. doi:10.1021/bi00731a011. PMID 4696755. 
  27. ↑ "Ligand-receptor interactions required for commitment to the activation of the interleukin 2 gene". Journal of Immunology 138 (7): 2169–2176. April 1987. doi:10.4049/jimmunol.138.7.2169. PMID 3104454. http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=3104454. 
  28. ↑ "The mitogenic lectin from Phaseolus vulgaris does not recognize the T3 antigen of human T lymphocytes". European Journal of Immunology 15 (5): 479–486. May 1985. doi:10.1002/eji.1830150512. PMID 3873340. 
  29. ↑ "Adherence of Escherichia coli to human mucosal cells mediated by mannose receptors". Nature 265 (5595): 623–625. February 1977. doi:10.1038/265623a0. PMID 323718. Bibcode: 1977Natur.265..623O. 
  30. ↑ "Interaction of concanavalin A with the cell wall of Bacillus subtilis". Journal of Bacteriology 109 (2): 652–658. February 1972. doi:10.1128/JB.109.2.652-658.1972. PMID 4621684. 
  31. ↑ "Identification of concanavalin A receptors and galactose-binding proteins in purified plasma membranes of Dictyostelium discoideum". The Journal of Cell Biology 74 (1): 264–273. July 1977. doi:10.1083/jcb.74.1.264. PMID 559679. 
  32. ↑ "Complex regulation of membrane-type matrix metalloproteinase expression and matrix metalloproteinase-2 activation by concanavalin A in MDA-MB-231 human breast cancer cells". Cancer Research 55 (15): 3272–3277. August 1995. PMID 7614461. 
  33. ↑ "Concanavalin A: a useful ligand for glycoenzyme immobilization--a review". Enzyme and Microbial Technology 13 (4): 290–295. April 1991. doi:10.1016/0141-0229(91)90146-2. PMID 1367163. 
  34. ↑ 34.0 34.1 "Lectin of Concanavalin A as an anti-hepatoma therapeutic agent". Journal of Biomedical Science 16 (1): 10. January 2009. doi:10.1186/1423-0127-16-10. PMID 19272170. 
  35. ↑ "[The characteristics of retina at the development of proliferative vitreoretinopathy in rats after intraocular injection of concanavalin a and dispase]". Rossiĭskii Fiziologicheskiĭ Zhurnal Imeni I.M. Sechenova 101 (5): 572–585. May 2015. PMID 26263683. 
  36. ↑ "Nonsteroid anti-inflammatory therapy suppresses the development of proliferative vitreoretinopathy more effectively than a steroid one". International Ophthalmology 38 (4): 1365–1378. August 2018. doi:10.1007/s10792-017-0594-3. PMID 28639085. 

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