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.
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.
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 α-macroglobulin (αM) family of proteins includes protease inhibitors,[11] typified by the humantetrameric 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 inhibitproteases 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 proteinsubstrates. 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 receptorbinding 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]
DiseaseEdit
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]
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.
ReferencesEdit
^ abcGRCh38: Ensembl release 89: ENSG00000175899 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000030111 - Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.
^ abDodds 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.
^ abArmstrong 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.
^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. PMC2267405. PMID 17608619.
^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.
^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.
^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.
^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.
^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.
^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. PMC281280. PMID 7693593.
^Liu, Nanmei; Lo, Louis Shi-li; Askary, S. Hassan; Jones, LaTrice; Kidane, Theodros Z.; Nguyen, Trisha Trang Minh; Goforth, Jeremy; Chu, Yu-Hsiang; Vivas, Esther; Tsai, Monta; Westbrook, Terence; Linder, Maria C. (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. PMC4286573. PMID 17363239.
^Liu, Nan-mei; Nguyen, Trang; Kidane, Theodros; Moriya, Mizue; Goforth, Jeremy; Chu, Andy; Linder, Maria (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.
^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.
^"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
^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.
alpha, macroglobulin, macroglobulin, α2m, alpha, macroglobulin, large, plasma, protein, found, blood, mainly, produced, liver, also, locally, synthesized, macrophages, fibroblasts, adrenocortical, cells, humans, encoded, gene, a2mavailable, structurespdborthol. a2 Macroglobulin a2M 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 A2MAvailable structuresPDBOrtholog search PDBe RCSBList of PDB id codes4ACQ 2P9R 1BV8IdentifiersAliasesA2M A2MD CPAMD5 FWP007 S863 7 transcuprein alpha 2 macroglobulinExternal IDsOMIM 103950 MGI 2449119 HomoloGene 37248 GeneCards A2MGene location Human Chr Chromosome 12 human 1 Band12p13 31Start9 067 664 bp 1 End9 116 229 bp 1 Gene location Mouse Chr Chromosome 6 mouse 2 Band6 F1 6 57 49 cMStart121 612 335 bp 2 End121 656 186 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inlower lobe of lungupper lobe of lungupper lobe of left lungright lungvisceral pleurapericardiumright coronary arterymucosa of urinary bladderascending aortaright ventricleTop expressed incorneal stromaciliary bodyirisretinal pigment epitheliumleft lung lobecervixatrioventricular valvemeningescerebellar vermisconjunctival fornixMore reference expression dataBioGPSn aGene ontologyMolecular functionpeptidase inhibitor activity interleukin 8 binding growth factor binding calcium dependent protein binding protease binding protein binding serine type endopeptidase inhibitor activity enzyme binding tumor necrosis factor binding endopeptidase inhibitor activity interleukin 1 binding signaling receptor binding GTPase activator activityCellular componentcytosol blood microparticle extracellular region extracellular exosome platelet alpha granule lumen extracellular space collagen containing extracellular matrixBiological processblood coagulation intrinsic pathway negative regulation of peptidase activity platelet degranulation extracellular matrix disassembly stem cell differentiation negative regulation of complement activation lectin pathway regulation of small GTPase mediated signal transduction positive regulation of GTPase activity negative regulation of endopeptidase activitySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez2232345EnsemblENSG00000175899ENSMUSG00000030111UniProtP01023Q6GQT1RefSeq mRNA NM 000014NM 001347423NM 001347424NM 001347425NM 175628RefSeq protein NP 000005NP 001334352NP 001334353NP 001334354NP 783327Location UCSC Chr 12 9 07 9 12 MbChr 6 121 61 121 66 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mousea2 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 a2 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 b insulin and IL 1b No specific deficiency with associated disease has been recognized and no disease state is attributed to low concentrations of a2 macroglobulin The concentration of a2 macroglobulin rises 10 fold or more in the nephrotic syndrome when other lower molecular weight proteins are lost in the urine The loss of a2 macroglobulin into urine is prevented by its large size The net result is that a2 macroglobulin reaches serum levels equal to or greater than those of albumin in the nephrotic syndrome which has the effect of maintaining oncotic pressure Contents 1 Structure 2 Function 3 Disease 4 References 5 External linksStructure EditHuman a2 macroglobulin is composed of four identical subunits bound together by S S bonds 5 6 In addition to tetrameric forms of a2 macroglobulin dimeric and more recently monomeric aM protease inhibitors have been identified 7 8 Each monomer of human a2 macroglobulin is composed of several functional domains including macroglobulin domains a thiol ester containing domain and a receptor binding domain 9 Overall a2 macroglobulin is the largest major nonimmunoglobulin protein in human plasma The amino acid sequence of a2 macroglobulin has been shown to be 71 the same as that of the pregnancy zone protein PZP also known as pregnancy associated a2 glycoprotein 10 Function EditThe a macroglobulin aM family of proteins includes protease inhibitors 11 typified by the human tetrameric a2 macroglobulin a2M 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 a2 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 aM protease inhibitors inhibit by steric hindrance 12 The mechanism involves protease cleavage of the bait region a segment of the aM that is particularly susceptible to proteolytic cleavage which initiates a conformational change such that the aM collapses about the protease In the resulting aM 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 aM protease complex to bind to clearance receptors and be removed from circulation 14 Tetrameric dimeric and more recently monomeric aM protease inhibitors have been identified 7 8 a2 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 a2 Macroglobulin has in its structure a 35 amino acid bait region Proteinases binding and cleaving the bait region become bound to a2M The proteinase a2M complex is recognised by macrophage receptors and cleared from the system Fibrinolysis simplified Blue arrows denote stimulation and red arrows inhibition a2 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 a2 macroglobulin 17 Disease Edita2 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 a2 macroglobulin is retained in the bloodstream Increased production of all proteins means a2 macroglobulin concentration increases This increase has little adverse effect on the health but is used as a diagnostic clue An increase in a2 Macroglobulin with normal amount of albumin mainly indicates acute and or chronic inflammation 19 A common variant 29 5 polymorphism of a2 macroglobulin leads to increased risk of Alzheimer s disease 20 21 a2 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 Edit a b c GRCh38 Ensembl release 89 ENSG00000175899 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000030111 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine 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 Sottrup Jensen L Stepanik TM Kristensen T Wierzbicki DM Jones CM Lonblad 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 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 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 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 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 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 Enghild JJ Salvesen G Thogersen 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 Enghild JJ Thogersen 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 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 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 Liu Nanmei Lo Louis Shi li Askary S Hassan Jones LaTrice Kidane Theodros Z Nguyen Trisha Trang Minh Goforth Jeremy Chu Yu Hsiang Vivas Esther Tsai Monta Westbrook Terence Linder Maria C 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 Liu Nan mei Nguyen Trang Kidane Theodros Moriya Mizue Goforth Jeremy Chu Andy Linder Maria 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 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 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 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 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 amp Pincus Henry s Clinical Diagnosis and Management by Laboratory Methods 21st ed Firestein Kelley s Textbook of Rheumatology 8th edition External links EditThe MEROPS online database for peptidases and their inhibitors I39 001 alpha 2 Macroglobulin at the U S National Library of Medicine Medical Subject Headings MeSH A2M human gene location in the UCSC Genome Browser A2M human gene details in the UCSC Genome Browser Retrieved from https en wikipedia org w index php title Alpha 2 Macroglobulin amp oldid 1171711929, wikipedia, wiki, book, books, library,
