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alpha-2-Macroglobulin

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α2-Macroglobulin (α2M) or alpha-2-macroglobulin is a large (720 KDa) plasma protein found in the blood. It is mainly produced by the liver, and also locally synthesized by macrophages, fibroblasts, and adrenocortical cells. In humans it is encoded by the A2M gene.

A2M
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesA2M, A2MD, CPAMD5, FWP007, S863-7, transcuprein, alpha-2-macroglobulin
External IDsOMIM: 103950; MGI: 2449119; HomoloGene: 37248; GeneCards: A2M; OMA:A2M - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2

232345

Ensembl

ENSG00000175899

ENSMUSG00000030111

UniProt

P01023

Q6GQT1

RefSeq (mRNA)

NM_000014
NM_001347423
NM_001347424
NM_001347425

NM_175628

RefSeq (protein)

NP_000005
NP_001334352
NP_001334353
NP_001334354

NP_783327

Location (UCSC)Chr 12: 9.07 – 9.12 MbChr 6: 121.61 – 121.66 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

α2-Macroglobulin acts as an antiprotease and is able to inactivate an enormous variety of proteinases. It functions as an inhibitor of fibrinolysis by inhibiting plasmin and kallikrein. It functions as an inhibitor of coagulation by inhibiting thrombin. α2-macroglobulin may act as a carrier protein because it also binds to numerous growth factors and cytokines, such as platelet-derived growth factor, basic fibroblast growth factor, TGF-β, insulin, and IL-1β.

No specific deficiency with associated disease has been recognized, and no disease state is attributed to low concentrations of α2-macroglobulin. The concentration of α2-macroglobulin rises 10-fold or more in the nephrotic syndrome when other lower molecular weight proteins are lost in the urine. The loss of α2-macroglobulin into urine is prevented by its large size. The net result is that α2-macroglobulin reaches serum levels equal to or greater than those of albumin in the nephrotic syndrome, which has the effect of maintaining oncotic pressure.

Structure

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Human α2-macroglobulin is composed of four identical subunits bound together by -S-S- bonds.[5][6] In addition to tetrameric forms of α2-macroglobulin, dimeric, and more recently monomeric αM protease inhibitors have been identified.[7][8]

Each monomer of human α2-macroglobulin is composed of several functional domains, including macroglobulin domains, a thiol ester-containing domain and a receptor-binding domain.[9] Overall, α2-macroglobulin is the largest major nonimmunoglobulin protein in human plasma.

The amino acid sequence of α2-macroglobulin has been shown to be 71% the same as that of the pregnancy zone protein (PZP; also known as pregnancy-associated α2-glycoprotein).[10]

Function

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The α-macroglobulin (αM) family of proteins includes protease inhibitors,[11] typified by the human tetrameric α2-macroglobulin (α2M); they belong to the MEROPS proteinase inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (1) the ability to inhibit proteases from all catalytic classes, (2) the presence of a 'bait region' (also known as a sequence of amino acids in an α2-macroglobulin molecule, or a homologous protein, that contains scissile peptide bonds for those proteinases that it inhibits) and a thiol ester, (3) a similar protease inhibitory mechanism and (4) the inactivation of the inhibitory capacity by reaction of the thiol ester with small primary amines. αM protease inhibitors inhibit by steric hindrance.[12] The mechanism involves protease cleavage of the bait region, a segment of the αM that is particularly susceptible to proteolytic cleavage, which initiates a conformational change such that the αM collapses about the protease. In the resulting αM-protease complex, the active site of the protease is sterically shielded, thus substantially decreasing access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (1) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (2) a major conformational change exposes a conserved COOH-terminal receptor binding domain [13] (RBD). RBD exposure allows the αM protease complex to bind to clearance receptors and be removed from circulation.[14] Tetrameric, dimeric, and, more recently, monomeric αM protease inhibitors have been identified.[7][8]

α2-Macroglobulin is able to inactivate an enormous variety of proteinases (including serine-, cysteine-, aspartic- and metalloproteinases). It functions as an inhibitor of fibrinolysis by inhibiting plasmin and kallikrein. It functions as an inhibitor of coagulation by inhibiting thrombin.[15] α2-Macroglobulin has in its structure a 35 amino acid "bait" region. Proteinases binding and cleaving the bait region become bound to α2M. The proteinase–α2M complex is recognised by macrophage receptors and cleared from the system.

 
Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.

α2-Macroglobulin is known to bind zinc, as well as copper in plasma, even more strongly than albumin, and such it is also known as transcuprein.[16] 10 to 15% of copper in human plasma is chelated by α2-macroglobulin.[17]

Disease

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α2-Macroglobulin levels are increased when the serum albumin levels are low,[18] which is most commonly seen in nephrotic syndrome, a condition wherein the kidneys start to leak out some of the smaller blood proteins. Because of its size, α2-macroglobulin is retained in the bloodstream. Increased production of all proteins means α2-macroglobulin concentration increases. This increase has little adverse effect on the health but is used as a diagnostic clue.

An increase in α2-Macroglobulin with normal amount of albumin mainly indicates acute and/or chronic inflammation.[19]

A common variant (29.5%) (polymorphism) of α2-macroglobulin leads to increased risk of Alzheimer's disease.[20][21]

α2-Macroglobulin binds to and removes the active forms of the gelatinase (MMP-2 and MMP-9) from the circulation via scavenger receptors on the phagocytes.

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000175899 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030111 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Andersen GR, Koch TJ, Dolmer K, Sottrup-Jensen L, Nyborg J (October 1995). "Low resolution X-ray structure of human methylamine-treated alpha 2-macroglobulin". J. Biol. Chem. 270 (42): 25133–41. doi:10.1074/jbc.270.42.25133. PMID 7559647. S2CID 86387917.
  6. ^ Sottrup-Jensen L, Stepanik TM, Kristensen T, Wierzbicki DM, Jones CM, Lønblad PB, et al. (1984). "Primary structure of human alpha 2-macroglobulin. V. The complete structure". J Biol Chem. 259 (13): 8318–27. doi:10.1016/S0021-9258(17)39730-2. PMID 6203908.
  7. ^ a b Dodds AW, Law SK (December 1998). "The phylogeny and evolution of the thioester bond-containing proteins C3, C4 and alpha 2-macroglobulin". Immunol. Rev. 166: 15–26. doi:10.1111/j.1600-065X.1998.tb01249.x. PMID 9914899. S2CID 84262599.
  8. ^ a b Armstrong PB, Quigley JP (1999). "Alpha2-macroglobulin: an evolutionarily conserved arm of the innate immune system". Dev. Comp. Immunol. 23 (4–5): 375–90. doi:10.1016/s0145-305x(99)00018-x. PMID 10426429.
  9. ^ Doan N, Gettins PG (2007). "Human alpha2-macroglobulin is composed of multiple domains, as predicted by homology with complement component C3". Biochem J. 407 (1): 23–30. doi:10.1042/BJ20070764. PMC 2267405. PMID 17608619.
  10. ^ Devriendt K, Van den Berghe H, Cassiman JJ, Marynen P (1991). "Primary structure of pregnancy zone protein. Molecular cloning of a full-length PZP cDNA clone by the polymerase chain reaction". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1088 (1): 95–103. doi:10.1016/0167-4781(91)90157-h. PMID 1989698.
  11. ^ Sottrup-Jensen L (July 1989). "Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation". J. Biol. Chem. 264 (20): 11539–42. doi:10.1016/S0021-9258(18)80094-1. PMID 2473064.
  12. ^ Enghild JJ, Salvesen G, Thøgersen IB, Pizzo SV (July 1989). "Proteinase binding and inhibition by the monomeric alpha-macroglobulin rat alpha 1-inhibitor-3". J. Biol. Chem. 264 (19): 11428–35. doi:10.1016/S0021-9258(18)60482-X. PMID 2472396.
  13. ^ Enghild JJ, Thøgersen IB, Roche PA, Pizzo SV (February 1989). "A conserved region in alpha-macroglobulins participates in binding to the mammalian alpha-macroglobulin receptor". Biochemistry. 28 (3): 1406–12. doi:10.1021/bi00429a069. PMID 2469470.
  14. ^ Van Leuven F, Cassiman JJ, Van den Berghe H (December 1986). "Human pregnancy zone protein and alpha 2-macroglobulin. High-affinity binding of complexes to the same receptor on fibroblasts and characterization by monoclonal antibodies". J. Biol. Chem. 261 (35): 16622–5. doi:10.1016/S0021-9258(18)66612-8. PMID 2430968.
  15. ^ de Boer JP, Creasey AA, Chang A, Abbink JJ, Roem D, Eerenberg AJ, Hack CE, Taylor FB (December 1993). "Alpha-2-macroglobulin functions as an inhibitor of fibrinolytic, clotting, and neutrophilic proteinases in sepsis: studies using a baboon model". Infect. Immun. 61 (12): 5035–43. doi:10.1128/iai.61.12.5035-5043.1993. PMC 281280. PMID 7693593.
  16. ^ Liu N, Lo LS, Askary SH, Jones L, Kidane TZ, Nguyen TT, Goforth J, Chu YH, Vivas E, Tsai M, Westbrook T, Linder MC (September 2007). "Transcuprein is a macroglobulin regulated by copper and iron availability". The Journal of Nutritional Biochemistry. 18 (9): 597–608. doi:10.1016/j.jnutbio.2006.11.005. PMC 4286573. PMID 17363239.
  17. ^ Liu Nm, Nguyen T, Kidane T, Moriya M, Goforth J, Chu A, Linder M (6 March 2006). "Transcupreins are serum copper-transporters of the macroglobulin family, and may be regulated by iron and copper". The FASEB Journal. 20 (4): A553–A554. doi:10.1096/fasebj.20.4.A553-d. ISSN 0892-6638. S2CID 90794136.
  18. ^ Stevenson FT, Greene S, Kaysen GA (January 1998). "Serum alpha 2-macroglobulin and alpha 1-inhibitor 3 concentrations are increased in hypoalbuminemia by post-transcriptional mechanisms". Kidney International. 53 (1): 67–75. doi:10.1046/j.1523-1755.1998.00734.x. PMID 9453001.
  19. ^ "Protein electrophoresis - serum". Icahn School of Medicine at Mount Sinai. Last reviewed on: 1/25/2022. Reviewed by: Todd Gersten, MD, and David Zieve, MD
  20. ^ Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RC, Perry R, Watson B, Bassett SS, McInnis MG, Albert MS, Hyman BT, Tanzi RE (August 1998). "Alpha-2 macroglobulin is genetically associated with Alzheimer disease". Nat. Genet. 19 (4): 357–60. doi:10.1038/1243. PMID 9697696. S2CID 15628847.
  21. ^ Kovacs DM (July 2000). "alpha2-macroglobulin in late-onset Alzheimer's disease". Exp. Gerontol. 35 (4): 473–9. doi:10.1016/S0531-5565(00)00113-3. PMID 10959035. S2CID 54409507.
  • McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods, 21st ed.
  • Firestein: Kelley's Textbook of Rheumatology, 8th edition.
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