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Concanavalin A

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"ConA" redirects here. For other uses, see Cona.
Concanavalin A
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 ensiformis (jackbean)
SymbolConA
PDB3CNA
UniProtP81461
Search for
StructuresSwiss-model
DomainsInterPro

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

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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 104–112 kDa 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]

For biotechnological uses, see Fluorescent glucose biosensors.

Maturation process

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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

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Concanavalin A interacts with diverse receptors containing mannose carbohydrates, notably rhodopsin, blood group markers, insulin receptors,[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 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

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  1. ^ a b PDB: 3CNA​; Hardman KD, Ainsworth CF (December 1972). "Structure of concanavalin A at 2.4-A resolution". Biochemistry. 11 (26): 4910–4919. 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. (eds.). The Lectins Properties, Functions and Applications in Biology and Medicine. Elsevier. pp. 33–247. ISBN 978-0-323-14444-5.
  3. ^ a b Sumner JB, Gralën N, Eriksson-Quensel IB (April 1938). "The Molecular Weights of Urease, Canavalin, Concanavalin a and Concanavalin B". Science. 87 (2261): 395–396. Bibcode:1938Sci....87..395S. doi:10.1126/science.87.2261.395. PMID 17746464.
  4. ^ a b c Dwyer JM, Johnson C (November 1981). "The use of concanavalin A to study the immunoregulation of human T cells". Clinical and Experimental Immunology. 46 (2): 237–249. PMC 1536405. PMID 6461456.
  5. ^ Schiefer HG, Krauss H, Brunner H, Gerhardt U (December 1975). "Ultrastructural visualization of surface carbohydrate structures on mycoplasma membranes by concanavalin A". Journal of Bacteriology. 124 (3): 1598–1600. doi:10.1128/JB.124.3.1598-1600.1975. PMC 236075. PMID 1104592.
  6. ^ GE Healthcare Life Sciences, Immobilized lectin Archived 2012-03-03 at the Wayback Machine[full citation needed]
  7. ^ Min W, Dunn AJ, Jones DH (April 1992). "Non-glycosylated recombinant pro-concanavalin A is active without polypeptide cleavage". The EMBO Journal. 11 (4): 1303–1307. doi:10.1002/j.1460-2075.1992.tb05174.x. PMC 556578. PMID 1563347.
  8. ^ Loris R, Hamelryck T, Bouckaert J, Wyns L (March 1998). "Legume lectin structure". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1383 (1): 9–36. doi:10.1016/S0167-4838(97)00182-9. PMID 9546043.
  9. ^ Krauss S, Buttgereit F, Brand MD (June 1999). "Effects of the mitogen concanavalin A on pathways of thymocyte energy metabolism". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1412 (2): 129–138. doi:10.1016/S0005-2728(99)00058-4. PMID 10393256.
  10. ^ Carrington DM, Auffret A, Hanke DE (1985). "Polypeptide ligation occurs during post-translational modification of concanavalin A". Nature. 313 (5997): 64–67. Bibcode:1985Natur.313...64C. doi:10.1038/313064a0. PMID 3965973. S2CID 4359482.
  11. ^ Hendrix RW (April 1991). "Protein carpentry". Current Biology. 1 (2): 71–73. doi:10.1016/0960-9822(91)90280-a. PMID 15336168. S2CID 45963307.
  12. ^ Nonis SG, Haywood J, Schmidberger JW, Mackie ER, Soares da Costa TP, Bond CS, Mylne JS (August 2021). "Structural and biochemical analyses of concanavalin A circular permutation by jack bean asparaginyl endopeptidase". The Plant Cell. 33 (8): 2794–2811. doi:10.1093/plcell/koab130. PMC 8408470. PMID 34235541.
  13. ^ Nonis SG, Haywood J, Mylne JS (April 2021). "Plant asparaginyl endopeptidases and their structural determinants of function". Biochemical Society Transactions. 49 (2): 965–976. doi:10.1042/BST20200908. PMC 8106488. PMID 33666219.
  14. ^ Cuatrecasas P, Tell GP (February 1973). "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. Bibcode:1973PNAS...70..485C. doi:10.1073/pnas.70.2.485. JSTOR 62526. PMC 433288. PMID 4510292.
  15. ^ Harmony JA, Cordes EH (November 1975). "Interaction of human plasma low density lipoprotein with concanavalin A and with ricin". The Journal of Biological Chemistry. 250 (22): 8614–8617. doi:10.1016/S0021-9258(19)40714-X. PMID 171260.[permanent dead link]
  16. ^ Betton GR (November 1976). "Agglutination reactions of spontaneous canine tumour cells, induced by concanavalin A, demonstrated by an isotopic assay". International Journal of Cancer. 18 (5): 687–696. doi:10.1002/ijc.2910180518. PMID 992901. S2CID 36612952.
  17. ^ Kakizoe T, Komatsu H, Niijima T, Kawachi T, Sugimura T (June 1980). "Increased agglutinability of bladder cells by concanavalin A after administration of carcinogens". Cancer Research. 40 (6): 2006–2009. PMID 7371036.
  18. ^ Becker FF, Shurgin A (October 1975). "Concanavalin A agglutination of cells from primary hepatocellular carcinomas and hepatic nodules induced by N-2-fluorenylacetamide". Cancer Research. 35 (10): 2879–2883. PMID 168971.
  19. ^ Inbar M, Ben-Bassat H, Sachs L (November 1971). "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. Bibcode:1971PNAS...68.2748I. doi:10.1073/pnas.68.11.2748. JSTOR 61219. PMC 389516. PMID 4330939.
  20. ^ Sela BA, Lis H, Sharon N, Sachs L (December 1971). "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. doi:10.1016/0005-2736(71)90132-5. PMID 4332414.
  21. ^ Gartner TK, Podleski TR (December 1975). "Evidence that a membrane bound lectin mediates fusion of L6 myoblasts". Biochemical and Biophysical Research Communications. 67 (3): 972–978. doi:10.1016/0006-291X(75)90770-6. PMID 1201086.
  22. ^ de Petris S (April 1975). "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. doi:10.1083/jcb.65.1.123. PMC 2111157. PMID 1092699.
  23. ^ Noonan KD, Burger MM (October 1973). "The relationship of concanavalin A binding to lectin-initiated cell agglutination". The Journal of Cell Biology. 59 (1): 134–142. doi:10.1083/jcb.59.1.134. PMC 2110924. PMID 4201706.
  24. ^ Capo C, Garrouste F, Benoliel AM, Bongrand P, Ryter A, Bell GI (August 1982). "Concanavalin-A-mediated thymocyte agglutination: a model for a quantitative study of cell adhesion". Journal of Cell Science. 56: 21–48. doi:10.1242/jcs.56.1.21. PMID 7166565.
  25. ^ Weiser MM (August 1972). "Concanavalin A agglutination of intestinal cells from the human fetus". Science. 177 (4048): 525–526. Bibcode:1972Sci...177..525W. doi:10.1126/science.177.4048.525. PMID 5050484. S2CID 23661797.
  26. ^ Cuatrecasas P (March 1973). "Interaction of wheat germ agglutinin and concanavalin A with isolated fat cells". Biochemistry. 12 (7): 1312–1323. doi:10.1021/bi00731a011. PMID 4696755.
  27. ^ Weiss A, Shields R, Newton M, Manger B, Imboden J (April 1987). "Ligand-receptor interactions required for commitment to the activation of the interleukin 2 gene". Journal of Immunology. 138 (7): 2169–2176. doi:10.4049/jimmunol.138.7.2169. PMID 3104454. S2CID 35173412.
  28. ^ Kanellopoulos JM, De Petris S, Leca G, Crumpton MJ (May 1985). "The mitogenic lectin from Phaseolus vulgaris does not recognize the T3 antigen of human T lymphocytes". European Journal of Immunology. 15 (5): 479–486. doi:10.1002/eji.1830150512. PMID 3873340. S2CID 21414006.
  29. ^ Ofek I, Mirelman D, Sharon N (February 1977). "Adherence of Escherichia coli to human mucosal cells mediated by mannose receptors". Nature. 265 (5595): 623–625. Bibcode:1977Natur.265..623O. doi:10.1038/265623a0. PMID 323718. S2CID 4223466.
  30. ^ Doyle RJ, Birdsell DC (February 1972). "Interaction of concanavalin A with the cell wall of Bacillus subtilis". Journal of Bacteriology. 109 (2): 652–658. doi:10.1128/JB.109.2.652-658.1972. PMC 285189. PMID 4621684.
  31. ^ West CM, McMahon D (July 1977). "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. doi:10.1083/jcb.74.1.264. PMC 2109878. PMID 559679.
  32. ^ Yu M, Sato H, Seiki M, Thompson EW (August 1995). "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. PMID 7614461.
  33. ^ Saleemuddin M, Husain Q (April 1991). "Concanavalin A: a useful ligand for glycoenzyme immobilization--a review". Enzyme and Microbial Technology. 13 (4): 290–295. doi:10.1016/0141-0229(91)90146-2. PMID 1367163.
  34. ^ a b Lei HY, Chang CP (January 2009). "Lectin of Concanavalin A as an anti-hepatoma therapeutic agent". Journal of Biomedical Science. 16 (1): 10. doi:10.1186/1423-0127-16-10. PMC 2644972. PMID 19272170.
  35. ^ Erdiakov AK, Tikhonovich MV, Rzhavina EM, Gavrilova SA (May 2015). "[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. PMID 26263683.
  36. ^ Tikhonovich MV, Erdiakov AK, Gavrilova SA (August 2018). "Nonsteroid anti-inflammatory therapy suppresses the development of proliferative vitreoretinopathy more effectively than a steroid one". International Ophthalmology. 38 (4): 1365–1378. doi:10.1007/s10792-017-0594-3. PMID 28639085. S2CID 4017540.
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