Skip to main content
SpringerLink
Log in

Changes Due to Ageing in the Glycan Structure of Alpha-2-Macroglobulin and Its Reactivity with Ligands

  • Published:
The Protein Journal Aims and scope Submit manuscript

Abstract

Alpha-2-macroglobulin (α2M) is a molecule generally associated with inflammation, and chronic inflammation is associated with ageing and cancer. The degree of inflammation was recently proposed to be considered as a biomarker of biological ageing. In this study, glycans attached to α2M were analysed in a human population of different ages by lectin-based protein microarray. Higher reactivity of α2M with several lectins was detected in older individuals indicating an increased content of specific monosaccharides: α2,6 sialic acid, mannose and N-acetylglucosamine, and multiantennary complex type N-glycans. The increased glycosylation of α2M was accompanied by reduced binding of Zn ions and insulin-like growth factor-binding protein 2 (IGFBP-2). Glycosylation of α2M and its reactivity with IGFBP-2 is similarly affected by ageing and incidence of colon cancer, but the reactivity of α2M with Zn ions is differently affected, as the binding of Zn ions remains unaltered in patients with colon cancer compared to healthy middle-aged individuals. Thus, the binding of IGFBP-2 to α2M seems to be related to structural changes in the glycan moieties of α2M, whereas binding of Zn ions, most likely, is not.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

α2M:

Alpha-2-macroglobulin

IGFBP-2:

Insulin-like growth factor-binding protein-2

SNA:

Sambucus nigra agglutinin

ConA:

Concanavalin A

MAL-II:

Maackia amurensis lectin-II

PHA-E:

Phaseolus vulgaris erythroagglutinin

WGA:

Wheat germ agglutinin

LCA:

Lens culinaris agglutinin

AAL:

Aleuria aurantia lectin

RCA-I:

Ricinus communis-I

LBPM:

Lectin-based protein microarray

IMAC:

Immobilised metal-affinity chromatography

DU:

Densitometric unit

References

  1. Ai X, Do A-T, Lozynska O, Kusche-Gullberg M, Lindahl U, Emerson CP (2003) QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling. J Cell Biol 162:341–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ashwell G, Harford J (1982) Carbohydrate-specific receptors of the liver. Annu Rev Biochem 51:531–554

    Article  CAS  PubMed  Google Scholar 

  3. Borth W (1994) Alpha 2 macroglobulin. A multifunctional binding and targeting protein with possible roles in immunity and autoimmunity. Ann N Y Acad Sci 737:267–272

    Article  CAS  PubMed  Google Scholar 

  4. Cross HS, Nittke T, Peterlik M (2009) Modulation of vitamin D synthesis and catabolism in colorectal carcinoma: a new target for cancer prevention. Anticancer Res 29:3705–3712

    CAS  PubMed  Google Scholar 

  5. Feizi T (1985) Demonstration by monoclonal antibodies that carbohydrate structures of glycoproteins and glycolipids are onco-developmental antigens. Nature 314:53–57

    Article  CAS  PubMed  Google Scholar 

  6. Foote JW, Delves HT (1984) Albumin bound and α2-macroglobulin bound zinc concentrations in the sera of healthy adults. J Clin Pathol 37:1050–1054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fougére B, Boulanger E, Nourhashémi F, Guyonnet S, Cesari M (2017) Chronic inflammation: Accelerator of biological aging. J Gerontol A 72:1218–1225

    Article  CAS  Google Scholar 

  8. Idei M, Miyake K, Horiuchi Y, Tabe Y, Miyake N, Ikeda N, Miida T (2010) Serum zinc concentration decreases with age and is associated with anemia in middle-aged and elderly people. Rinsho Byori 58:205–210

    CAS  PubMed  Google Scholar 

  9. James K (1990) Interactions between cytokines and alpha-2-macroglobulin. Immunol Today 11:163–166

    Article  CAS  PubMed  Google Scholar 

  10. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  11. Kahari VM, Saarialho-Kere U (1999) Matrix metalloproteinase and their inhibitors in tumor growth and invasion. Ann Med 31:34–45

    Article  CAS  PubMed  Google Scholar 

  12. Kim YJ, Varki A (1997) Perspectives on the significance of altered glycosylation of glycoproteins in cancer. Glycoconj J 14:569–576

    Article  CAS  PubMed  Google Scholar 

  13. Kovacs DM (2000) α2-Macroglobulin in late-onset Alzheimer’s disease. Exp Gerontol 35:473–479

    Article  CAS  PubMed  Google Scholar 

  14. Lin Z, Lo A, Simeone DM, Ruffin MT, Lubman DM (2012) An N-glycosylation analysis of human alpha-2-macroglobulin using an integrated approach. J Proteom Bioinform 5:127–134

    Article  CAS  Google Scholar 

  15. Matoska J, Wahlstrom T, Vaheri A, Bizik J, Grofova M (1988) Tumor-associated alpha-2-macroglobulin in human melanomas. Int J Cancer 41:359–363

    Article  CAS  PubMed  Google Scholar 

  16. Mattenburg JM, Webb DJ, Gonias SL (2002) Distinct binding sites in the structure of α2-macroglobulin mediate the interaction with β-amyloid peptide and growth factors. J Biol Chem 277:13338–13345

    Article  CAS  Google Scholar 

  17. Mehrian-Shai R, Chen CD, Shi T, Horvath S, Nelson SF, Reichardt JKV, Sawyers CL (2007) Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. PNAS 104:5563–5568

    Article  CAS  PubMed  Google Scholar 

  18. Mocchegiani E, Costarelli L, Giacconi R, Cipriano C, Muti E, Malavolta M (2006) Zinc-binding proteins (metallothionein and α-2 macroglobulin) and immunosenescence. Exp Gerontol 41:1094–1107

    Article  CAS  PubMed  Google Scholar 

  19. Moroni F, Di Paolo ML, Rigo A, Cipriano C, Giacconi R, Recchioni R, Marcheselli F, Malavolta M, Mocchegiani E (2005) Interrelationship among neutrophil efficiency, inflammation, antioxidant activity and zinc pool in very old age. Biogerontology 6:271–281

    Article  CAS  PubMed  Google Scholar 

  20. Ohtsubo K, Marth JD (2006) Glycosylation in cellular mechanisms of health and disease. Cell 126:855–867

    Article  CAS  PubMed  Google Scholar 

  21. Partridge EA, Le Roy C, Di Guglielmo GM, Pawling J, Cheung P, Granovsky M, Nabi IR, Wrana JL, Dennis JW (2004) Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306:120–124

    Article  CAS  PubMed  Google Scholar 

  22. Rehman AA, Ahsan H, Khan FH (2013) α-2-Macroglobulin: a physiological guardian. J Cell Physiol 228:1665–1675

    Article  CAS  PubMed  Google Scholar 

  23. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK (2000) SEER cancer statistics review, 1973–1998. National Institute of Health; NIH Publication 00-2789

  24. Rink L, Seyfart M (1997) Characteristics of immunologic tests values in the elderly. Z Gerontol Geriatr 30:220–225

    CAS  PubMed  Google Scholar 

  25. Stadtman ER (2001) Protein oxidation in aging and age-related diseases. Ann N Y Acad Sci 928:22–38

    Article  CAS  PubMed  Google Scholar 

  26. Šunderić M, Mihailović N, Nedić O (2014) Protein molecular forms of insulin-like growth factor binding protein-2 change with aging. Exp Gerontol 58:154–158

    Article  CAS  PubMed  Google Scholar 

  27. Šunderić M, Miljuš G, Nedić O (2013) Interaction of Insulin-Like Growth Factor-Binding Protein 2 with α2-Macroglobulin in the Circulation. Protein J 32:138–142

    Article  CAS  PubMed  Google Scholar 

  28. Šunderić M, Sedivá A, Robajac D, Miljuš G, Gemeiner P, Nedić O, Katrlik J (2016) Lectin-based protein microarray analysis of differences in serum alpha-2-macroglobulin glycosylation between patients with colorectal cancer and persons without cancer. Biotechnol Appl Biochem 63:457–464

    Article  CAS  PubMed  Google Scholar 

  29. Thieme R, Kurz S, Kolb M, Debebe T, Holtze S, Morhart M, Huse K, Szafranski K, Platzer M, Hildebrandt TB, Birkenmeier G (2015) Analysis of alpha-2 macroglobulin from the long-lived and cancer-resistant naked mole-rat and human plasma. PLoS ONE. https://doi.org/10.1371/journal.pone.0130470

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tuohimaa P (2009) Vitamin D and aging. J Steroid Biochem Mol Biol 114:78–84

    Article  CAS  PubMed  Google Scholar 

  31. Vanhooren V, Dewaele S, Libert C, Engelborghs S, De Deyn PP, Toussaint O, Debacq-Chainiaux F, Poulain M, Glupczynski Y, Franceschi C, Jaspers K, van der Pluijm I, Hoeijmakers J, Chen CC (2010) Serum N-glycan profile shift during human ageing. Exp Gerontol 45:738–743

    Article  CAS  PubMed  Google Scholar 

  32. Weaving G, Batstone GF, Jones RG (2016) Age and sex variation in serum albumin concentration: an observational study. Ann Clin Biochem 53:106–111

    Article  CAS  PubMed  Google Scholar 

  33. Yancik R, Holmes ME (2002) NIA/NCI Report of the Cancer Center Workshop (June 13–15, 2001). Exploring the role of cancer centers for integrating aging and cancer research

Download references

Acknowledgements

This work was supported by the bilateral cooperation Grants (451-03-545/2015-09/01, SK-SRB-2016-0023), APVV SK-SRB-2013-0028 and APVV SK-SRB-2016-0023, and by national Grant Nos. 173042 (Ministry of Education, Science and Technological Development of the Republic of Serbia), VEGA 2/0162/14 and APVV-14-0753. The authors would like to thank Dr Judith Anna Nikolić, a native English speaker for language corrections.

Author information

Authors and Affiliations

  1. Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia

    Miloš Šunderić, Danica Ćujić & Olgica Nedić

  2. Department of Glycobiotechnology, Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia

    Martina Križáková & Jaroslav Katrlík

  3. Clinical-Medical Centre “Bežanijska Kosa”, Belgrade, Serbia

    Vesna Malenković

Authors
  1. Miloš Šunderić
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martina Križáková
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vesna Malenković
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Danica Ćujić
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jaroslav Katrlík
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Olgica Nedić
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miloš Šunderić.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Šunderić, M., Križáková, M., Malenković, V. et al. Changes Due to Ageing in the Glycan Structure of Alpha-2-Macroglobulin and Its Reactivity with Ligands. Protein J 38, 23–29 (2019). https://doi.org/10.1007/s10930-018-9806-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10930-018-9806-6

Keywords

Search

Navigation