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Gene Review

A2M  -  alpha-2-macroglobulin

Homo sapiens

Synonyms: A2MD, Alpha-2-M, Alpha-2-macroglobulin, C3 and PZP-like alpha-2-macroglobulin domain-containing protein 5, CPAMD5, ...
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Disease relevance of A2M

  • Inhibition of t-PA and alpha 2M* binding to LRP/alpha 2MR on rat hepatoma MH1C1 cells are shown to require amino acid residues 18-24 and 100-107 on the 39-kDa protein [1].
  • Preincubation of permeabilized macrophages with GDP beta S abrogated the effects of GTP gamma S. Our results suggest that the signaling alpha 2M receptor is coupled to a pertussis toxin-insensitive G protein and possibly to a cholera toxin-sensitive G protein [2].
  • Ni2+ also inhibited the binding of trypsin-activated alpha 2-macroglobulin to SMC but did not affect the binding of RAP, Pseudomonas exotoxin A, or low-density lipoproteins [3].
  • Polymyxin B-conjugated alpha 2-macroglobulin as an adjunctive therapy to sepsis: Modes of action and impact on lethality [4].
  • Serum alpha 2M was greater in dialysis-related amyloidosis than in control patients (t = 2.35; P < 0.026) [5].

Psychiatry related information on A2M


High impact information on A2M


Chemical compound and disease context of A2M


Biological context of A2M

  • We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule [6].
  • RESULTS: Comparison of allele, genotype, and haplotype frequencies for polymorphisms in A2M revealed no significant differences between patients and control subjects [18].
  • We have prepared conjugates of polymyxin B (PMB) and the cytokine binding protein alpha2-macroglobulin (A2M) [4].
  • We analyzed the frequency of two polymorphisms in the A2M (Val 1000 Ile, Exon 18 del), and one polymorphism in the LRP (A216V) gene in a case control study involving 326 MS patients, and 290 controls, all defined for the expression of HLA-DR15 [19].
  • We examined the distribution of A2M genotypes and alleles in a cohort of 146 AD patients and 160 age-matched non-demented individuals [20].

Anatomical context of A2M


Associations of A2M with chemical compounds


Physical interactions of A2M

  • A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP [6].
  • Thus, our studies demonstrate several specific regions on the 39-kDa protein which are required for the inhibition of t-PA and alpha 2M* binding to LRP/alpha 2MR [1].
  • These findings indicate that "F" alpha 2M interacts with IL-1 beta through a thiol-disulfide exchange reaction [28].
  • When the macrophages were incubated with(125)I-rhIL-8-alpha-2-M complexes there was a significant amount of IL-8 associated with the cells [29].
  • The PSA bound to alpha 2-M is caged by the inhibitor and thus escapes detection by antibodies [30].

Enzymatic interactions of A2M


Regulatory relationships of A2M


Other interactions of A2M

  • Activated C3 and alpha 2M may function as IL-1 beta carrier proteins in biologic fluids, in addition to their other physiologic roles [36].
  • The findings provide evidence that the alpha 2M receptor and LRP are the same molecule [37].
  • It is possible that heparin-like molecules released from extracellular matrixes could prevent the inactivation of VEGF by alpha 2M resulting in the potentiation of processes such as tumor angiogenesis [26].
  • This multifunctional receptor is the major neuronal receptor both for apolipoprotein E (apoE, protein; APOE, gene) and for alpha2-macroglobulin (alpha2M, protein; A2M, gene), and it mediates clearance of apoE/A beta and alpha2M/A beta complexes [38].
  • Inhibition experiments indicated that the streptococcal binding site for alpha 2M differed from the receptors for immunoglobulin G, fibrinogen, aggregated beta 2-microglobulin, albumin, and fibronectin [39].

Analytical, diagnostic and therapeutic context of A2M

  • An additional component of this receptor system is a 39-kDa polypeptide that co-purifies with the alpha 2M receptor during affinity chromatography [37].
  • Further evidence comes from immunoprecipitation experiments using a monoclonal antibody specific for the alpha 2M receptor that show this molecule, like LRP, to contain two polypeptides of approximately 420 and 85 kDa that are noncovalently associated [37].
  • Plasma samples which were subjected to non-denaturing PAGE and autoradiography demonstrated binding of both growth factors exclusively to the slow-form of alpha 2M [40].
  • By immunoelectron microscopy we found that after 30 min at 37 degrees C most of the detected alpha 2M* (70% of the total gold particles) was inside the cells and associated with endosomal vesicles [41].
  • The cleavage site of PSA in alpha 2-M was analyzed by SDS-PAGE and microsequencing [30].


  1. Identification of domains on the 39-kDa protein that inhibit the binding of ligands to the low density lipoprotein receptor-related protein. Warshawsky, I., Bu, G., Schwartz, A.L. J. Biol. Chem. (1993) [Pubmed]
  2. Evidence for a second alpha 2-macroglobulin receptor. Misra, U.K., Chu, C.T., Gawdi, G., Pizzo, S.V. J. Biol. Chem. (1994) [Pubmed]
  3. Nickel is a specific inhibitor for the binding of activated alpha 2-macroglobulin to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. Hussain, M.M., Kancha, R.K., Tulenko, T.N. Biochemistry (1995) [Pubmed]
  4. Polymyxin B-conjugated alpha 2-macroglobulin as an adjunctive therapy to sepsis: Modes of action and impact on lethality. Birkenmeier, G., Nicklisch, S., Pockelt, C., Mossie, A., Steger, V., Gläser, C., Hauschildt, S., Usbeck, E., Huse, K., Sack, U., Bauer, M., Schäfer, A. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  5. Serum alpha 2-macroglobulin in haemodialysis patients: baseline and kinetic studies. Argilés, A., Kerr, P.G., Mourad, G., Mion, C.M., Atkins, R.C. Nephrol. Dial. Transplant. (1993) [Pubmed]
  6. Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease. Liao, A., Nitsch, R.M., Greenberg, S.M., Finckh, U., Blacker, D., Albert, M., Rebeck, G.W., Gomez-Isla, T., Clatworthy, A., Binetti, G., Hock, C., Mueller-Thomsen, T., Mann, U., Zuchowski, K., Beisiegel, U., Staehelin, H., Growdon, J.H., Tanzi, R.E., Hyman, B.T. Hum. Mol. Genet. (1998) [Pubmed]
  7. Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Sleegers, K., Roks, G., Theuns, J., Aulchenko, Y.S., Rademakers, R., Cruts, M., van Gool, W.A., Van Broeckhoven, C., Heutink, P., Oostra, B.A., van Swieten, J.C., van Duijn, C.M. Brain (2004) [Pubmed]
  8. Complexing of tissue plasminogen activator with PAI-1, alpha 2-macroglobulin, and C1-inhibitor: studies in patients with defibrination and a fibrinolytic state after electroshock or complicated labor. Bennett, B., Croll, A., Ferguson, K., Booth, N.A. Blood (1990) [Pubmed]
  9. Antiproteases and Down's syndrome in an Australian population. McPhee, H., Ananthakrishnan, R., Taft, L.I. J. Med. Genet. (1980) [Pubmed]
  10. Increased alpha-2-macroglobulin in opiate addicts: further evidence of an alteration in the coagulation system due to opiate addiction. Ceriello, A., Dello Russo, P., Curcio, F., Passariello, N., Giugliano, D. Acta Haematol. (1985) [Pubmed]
  11. Alpha-2 macroglobulin gene and Alzheimer disease. Rudrasingham, V., Wavrant-De Vrièze, F., Lambert, J.C., Chakraverty, S., Kehoe, P., Crook, R., Amouyel, P., Wu, W., Rice, F., Pérez-Tur, J., Frigard, B., Morris, J.C., Carty, S., Petersen, R., Cottel, D., Tunstall, N., Holmans, P., Lovestone, S., Chartier-Harlin, M.C., Goate, A., Hardy, J., Owen, M.J., Williams, J. Nat. Genet. (1999) [Pubmed]
  12. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Blacker, D., Wilcox, M.A., Laird, N.M., Rodes, L., Horvath, S.M., Go, R.C., Perry, R., Watson, B., Bassett, S.S., McInnis, M.G., Albert, M.S., Hyman, B.T., Tanzi, R.E. Nat. Genet. (1998) [Pubmed]
  13. Segregation of transferrin to a mildly acidic (pH 6.5) para-Golgi compartment in the recycling pathway. Yamashiro, D.J., Tycko, B., Fluss, S.R., Maxfield, F.R. Cell (1984) [Pubmed]
  14. A modified human alpha 2-macroglobulin derivative that binds tumor necrosis factor-alpha and interleukin-1 beta with high affinity in vitro and reverses lipopolysaccharide toxicity in vivo in mice. Webb, D.J., Gonias, S.L. Lab. Invest. (1998) [Pubmed]
  15. Inhibition of intracellular proteolytic processing of soluble proproteins by an engineered alpha 2-macroglobulin containing a furin recognition sequence in the bait region. Van Rompaey, L., Ayoubi, T., Van De Ven, W., Marynen, P. Biochem. J. (1997) [Pubmed]
  16. Serum alpha 2-macroglobulin and alpha 1-inhibitor 3 concentrations are increased in hypoalbuminemia by post-transcriptional mechanisms. Stevenson, F.T., Greene, S., Kaysen, G.A. Kidney Int. (1998) [Pubmed]
  17. Temperature-dependent biosynthesis of thiol esters in baculovirus recombinant alpha 2M and PZP. Van Rompaey, L., Marynen, P. Ann. N. Y. Acad. Sci. (1994) [Pubmed]
  18. Association study of the A2M and LRP1 Genes with Alzheimer disease in the Han Chinese. Bian, L., Yang, J.D., Guo, T.W., Duan, Y., Qin, W., Sun, Y., Feng, G.Y., He, L. Biol. Psychiatry (2005) [Pubmed]
  19. No association of three polymorphisms in the alpha-2-macroglobulin and lipoprotein related receptor genes with multiple sclerosis. Schweer, D., Jacobsen, M., Ziegler, A., Jäkel, S., Oertel, W.H., Sommer, N., Hemmer, B. J. Neuroimmunol. (2001) [Pubmed]
  20. Alpha-2 macroglobulin gene in early- and late-onset Alzheimer disease. Korovaitseva, G.I., Premkumar, S., Grigorenko, A., Molyaka, Y., Galimbet, V., Selezneva, N., Gavrilova, S.I., Farrer, L.A., Rogaev, E.I. Neurosci. Lett. (1999) [Pubmed]
  21. The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor binds and mediates catabolism of bovine milk lipoprotein lipase. Chappell, D.A., Fry, G.L., Waknitz, M.A., Iverius, P.H., Williams, S.E., Strickland, D.K. J. Biol. Chem. (1992) [Pubmed]
  22. Alpha 2-macroglobulin is a binding protein for basic fibroblast growth factor. Dennis, P.A., Saksela, O., Harpel, P., Rifkin, D.B. J. Biol. Chem. (1989) [Pubmed]
  23. Human T cell responses against the major cysteine proteinase (cruzipain) of Trypanosoma cruzi: role of the multifunctional alpha 2-macroglobulin receptor in antigen presentation by monocytes. Morrot, A., Strickland, D.K., Higuchi, M.d.e. .L., Reis, M., Pedrosa, R., Scharfstein, J. Int. Immunol. (1997) [Pubmed]
  24. alpha 2-Macroglobulin synthesis by the human monocytic cell line THP-1 is differentiation state-dependent. Lysiak, J.J., Hussaini, I.M., Gonias, S.L. J. Cell. Biochem. (1997) [Pubmed]
  25. Genetic association of argyrophilic grain disease with polymorphisms in alpha-2 macroglobulin and low-density lipoprotein receptor-related protein genes. Ghebremedhin, E., Schultz, C., Thal, D.R., Del Tredici, K., Rueb, U., Braak, H. Neuropathol. Appl. Neurobiol. (2002) [Pubmed]
  26. Vascular endothelial growth factor is inactivated by binding to alpha 2-macroglobulin and the binding is inhibited by heparin. Soker, S., Svahn, C.M., Neufeld, G. J. Biol. Chem. (1993) [Pubmed]
  27. Clearance of chylomicron remnants by the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. Hussain, M.M., Maxfield, F.R., Más-Oliva, J., Tabas, I., Ji, Z.S., Innerarity, T.L., Mahley, R.W. J. Biol. Chem. (1991) [Pubmed]
  28. Identification of alpha 2-macroglobulin as a cytokine binding plasma protein. Binding of interleukin-1 beta to "F" alpha 2-macroglobulin. Borth, W., Luger, T.A. J. Biol. Chem. (1989) [Pubmed]
  29. Involvement of alpha-2-macroglobulin receptor in clearance of interleukin 8-alpha-2-macroglobulin complexes by human alveolar macrophages. Kurdowska, A., Alden, S.M., Noble, J.M., Stevens, M.D., Carr, F.K. Cytokine (2000) [Pubmed]
  30. Prostate-specific antigen forms complexes with human alpha 2-macroglobulin and binds to the alpha 2-macroglobulin receptor/LDL receptor-related protein. Otto, A., Bär, J., Birkenmeier, G. J. Urol. (1998) [Pubmed]
  31. Interaction of human plasma kallikrein and its light chain with alpha 2-macroglobulin. van der Graaf, F., Rietveld, A., Keus, F.J., Bouma, B.N. Biochemistry (1984) [Pubmed]
  32. Alpha-1 antichymotrypsin and alpha-2 macroglobulin gene polymorphisms are not associated with Korean late-onset Alzheimer's disease. Ki, C.S., Na, D.L., Kim, H.J., Kim, J.W. Neurosci. Lett. (2001) [Pubmed]
  33. Modulation of the alpha 2 macroglobulin receptor/low density lipoprotein receptor related protein by interferon-gamma in human astroglial cells. Businaro, R., Fabrizi, C., Persichini, T., Starace, G., Ennas, M.G., Fumagalli, L., Lauro, G.M. J. Neuroimmunol. (1997) [Pubmed]
  34. Alpha 2-macroglobulin and pregnancy zone protein. Serum levels, alpha 2-macroglobulin receptors, cellular synthesis and aspects of function in relation to immunology. Petersen, C.M. Danish medical bulletin. (1993) [Pubmed]
  35. The mammalian low-density lipoprotein receptor family. Hussain, M.M., Strickland, D.K., Bakillah, A. Annu. Rev. Nutr. (1999) [Pubmed]
  36. Binding of recombinant interleukin-1 beta to the third complement component and alpha 2-macroglobulin after activation of serum by immune complexes. Borth, W., Urbanski, A., Prohaska, R., Susanj, M., Luger, T.A. Blood (1990) [Pubmed]
  37. Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. Strickland, D.K., Ashcom, J.D., Williams, S., Burgess, W.H., Migliorini, M., Argraves, W.S. J. Biol. Chem. (1990) [Pubmed]
  38. Role of the low-density lipoprotein receptor-related protein in beta-amyloid metabolism and Alzheimer disease. Hyman, B.T., Strickland, D., Rebeck, G.W. Arch. Neurol. (2000) [Pubmed]
  39. Characterization of binding of human alpha 2-macroglobulin to group G streptococci. Chhatwal, G.S., Müller, H.P., Blobel, H. Infect. Immun. (1983) [Pubmed]
  40. Binding of platelet-derived growth factor-BB and transforming growth factor-beta 1 to alpha 2-macroglobulin in vitro and in vivo: comparison of receptor-recognized and non-recognized alpha 2-macroglobulin conformations. Crookston, K.P., Webb, D.J., Lamarre, J., Gonias, S.L. Biochem. J. (1993) [Pubmed]
  41. Lipoprotein lipase-mediated uptake of lipoprotein in human fibroblasts: evidence for an LDL receptor-independent internalization pathway. Fernández-Borja, M., Bellido, D., Vilella, E., Olivecrona, G., Vilaró, S. J. Lipid Res. (1996) [Pubmed]
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