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Alpha-2-Macroglobulin
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==Function== The [[α-macroglobulin]] (αM) [[protein family|family of proteins]] includes [[protease inhibitor (biology)|protease inhibitor]]s,<ref name="SottrupJensen_1989">{{cite journal | vauthors = Sottrup-Jensen L | title = Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation | journal = Journal of Biological Chemistry | volume = 264 | issue = 20 | pages = 11539–11542 | date = July 1989 | pmid = 2473064 | doi = 10.1016/S0021-9258(18)80094-1 | doi-access = free }}</ref> typified by the [[Homo sapiens|human]] [[tetrameric protein|tetrameric]] α<sub>2</sub>-macroglobulin (α<sub>2</sub>M); they belong to the MEROPS [[proteinase]] inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (1) the ability to [[Enzyme inhibitor|inhibit]] [[protease]]s from all [[catalytic]] classes, (2) the presence of a 'bait region' (also known as a sequence of [[amino acids]] in an α<sub>2</sub>-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 [[amine]]s. αM [[Protease inhibitor (biology)|protease inhibitor]]s inhibit by [[steric]] hindrance.<ref name="Enghild_1989">{{cite journal | vauthors = Enghild JJ, Salvesen G, Thøgersen IB, Pizzo SV | title = Proteinase binding and inhibition by the monomeric alpha-macroglobulin rat alpha 1-inhibitor-3 | journal = Journal of Biological Chemistry | volume = 264 | issue = 19 | pages = 11428–11435 | date = July 1989 | pmid = 2472396 | doi = 10.1016/S0021-9258(18)60482-X | doi-access = free }}</ref> The [[Nuclear receptor#Mechanism of action|mechanism]] involves protease [[Bond cleavage|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 [[steric effects|sterically]] shielded, thus substantially decreasing access to [[protein]] [[substrate (biochemistry)|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 [[Protein structure|conformational]] change exposes a [[conserved sequence|conserved]] [[COOH-terminal]] [[receptor (biochemistry)|receptor]] [[Binding (molecular)|binding]] domain <ref name="Enghild_1989a">{{cite journal | vauthors = Enghild JJ, Thøgersen IB, Roche PA, Pizzo SV | title = A conserved region in alpha-macroglobulins participates in binding to the mammalian alpha-macroglobulin receptor | journal = Biochemistry | volume = 28 | issue = 3 | pages = 1406–1412 | date = February 1989 | pmid = 2469470 | doi = 10.1021/bi00429a069 }}</ref> (RBD). RBD exposure allows the αM protease [[Protein complex|complex]] to [[Molecular binding|bind]] to clearance [[Receptor (biochemistry)|receptors]] and be removed from circulation.<ref name="Van_Leuven_1986">{{cite journal | vauthors = Van Leuven F, Cassiman JJ, Van den Berghe H | title = Human pregnancy zone protein and alpha 2-macroglobulin. High-affinity binding of complexes to the same receptor on fibroblasts and characterization by monoclonal antibodies | journal = Journal of Biological Chemistry | volume = 261 | issue = 35 | pages = 16622–16625 | date = December 1986 | pmid = 2430968 | doi = 10.1016/S0021-9258(18)66612-8 | doi-access = free }}</ref> Tetrameric, dimeric, and, more recently, monomeric αM protease inhibitors have been identified.<ref name="Dodds_1998" /><ref name="Armstrong_1999" /> α<sub>2</sub>-Macroglobulin is able to inactivate an enormous variety of proteinases (including [[serine proteinase|serine]]-, [[cysteine-proteinase|cysteine]]-, [[aspartic proteinase|aspartic]]- and [[metalloproteinase]]s). It functions as an inhibitor of [[fibrinolysis]] by inhibiting [[plasmin]] and kallikrein. It functions as an inhibitor of [[coagulation]] by inhibiting [[thrombin]].<ref name="de_Boer_1993">{{cite journal | vauthors = de Boer JP, Creasey AA, Chang A, Abbink JJ, Roem D, Eerenberg AJ, Hack CE, Taylor FB | title = Alpha-2-macroglobulin functions as an inhibitor of fibrinolytic, clotting, and neutrophilic proteinases in sepsis: studies using a baboon model | journal = Infection and Immunity | volume = 61 | issue = 12 | pages = 5035–5043 | date = December 1993 | pmid = 7693593 | pmc = 281280 | doi = 10.1128/iai.61.12.5035-5043.1993 }}</ref> α<sub>2</sub>-Macroglobulin has in its structure a 35 amino acid "bait" region. Proteinases binding and cleaving the bait region become bound to α<sub>2</sub>M. The proteinase–α<sub>2</sub>M complex is recognised by macrophage receptors and cleared from the system. [[Image:Fibrinolysis.svg|center|framed|Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.]] α<sub>2</sub>-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'''.<ref>{{cite journal | vauthors = Liu N, Lo LS, Askary SH, Jones L, Kidane TZ, Nguyen TT, Goforth J, Chu YH, Vivas E, Tsai M, Westbrook T, Linder MC | title = Transcuprein is a macroglobulin regulated by copper and iron availability | journal = The Journal of Nutritional Biochemistry | volume = 18 | issue = 9 | pages = 597–608 | date = September 2007 | pmid = 17363239 | pmc = 4286573 | doi = 10.1016/j.jnutbio.2006.11.005 }}</ref> 10 to 15% of copper in human plasma is chelated by α<sub>2</sub>-macroglobulin.<ref>{{cite journal | vauthors = Liu NM, Nguyen T, Kidane T, Moriya M, Goforth J, Chu A, Linder M | title = Transcupreins are serum copper-transporters of the macroglobulin family, and may be regulated by iron and copper | journal = The FASEB Journal | volume = 20 | issue = 4 | pages = A553–A554 | date = 6 March 2006 | doi = 10.1096/fasebj.20.4.A553-d | language = en | issn = 0892-6638 | s2cid = 90794136 | doi-access = free }}</ref>
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