Abstract
α2-macroglobulins are broad-spectrum endopeptidase inhibitors, which have to date been characterised from metazoans (vertebrates and invertebrates) and Gram-negative bacteria. Their structural and biochemical properties reveal two related modes of action: the “Venus flytrap” and the “snap-trap” mechanisms. In both cases, peptidases trigger a massive conformational rearrangement of α2-macroglobulin after cutting in a highly flexible bait region, which results in their entrapment. In some homologs, a second action takes place that involves a highly reactive β-cysteinyl-γ-glutamyl thioester bond, which covalently binds cleaving peptidases and thus contributes to the further stabilization of the enzyme:inhibitor complex. Trapped peptidases are still active, but have restricted access to their substrates due to steric hindrance. In this way, the human α2-macroglobulin homolog regulates proteolysis in complex biological processes, such as nutrition, signalling, and tissue remodelling, but also defends the host organism against attacks by external toxins and other virulence factors during infection and envenomation. In parallel, it participates in several other biological functions by modifying the activity of cytokines and regulating hormones, growth factors, lipid factors and other proteins, which has a great impact on physiology. Likewise, bacterial α2-macroglobulins may participate in defence by protecting cell wall components from attacking peptidases, or in host-pathogen interactions through recognition of host peptidases and/or antimicrobial peptides. α2-macroglobulins are more widespread than initially thought and exert multifunctional roles in both eukaryotes and prokaryotes, therefore, their on-going study is essential.
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References
Abe K, Yamamoto K, Sinohara H (1989) Proteinase inhibitory spectrum of mouse murinoglobulin and alpha-macroglobulin. J Biochem 106:564–568
Anai K, Sugiki M, Yoshida E, Maruyama M (1998) Inhibition of a snake venom hemorrhagic metalloproteinase by human and rat alpha-macroglobulins. Toxicon 36(8):1127–1139
Andersen GR, Jacobsen L, Thirup S, Nyborg J, Sottrup-Jensen L (1991) Crystallization and preliminary X-ray analysis of methylamine-treated alpha-2-macroglobulin and 3 alpha-2-macroglobulin-proteinase complexes. FEBS Lett 292:267–270
Andersen GR, Koch T, Sørensen AH, Thirup S, Nyborg J, Dolmer K, Linda J, Sottrup-Jensen L (1994) Crystallisation of proteins of the alpha-2-macroglobulin superfamily. Ann N Y Acad Sci 737:444–446
Andersen GR, Koch T, Dolmer K, Sottrup-Jensen L, Nyborg J (1995) Low resolution X-ray structure of human methylamine-treated alpha-2-macroglobulin. J Biol Chem 270(42):25133–25141
Andersen OM, Christensen LL, Christensen PA, Sorensen ES, Jacobsen C, Moestrup SK, Etzerodt M, Thogersen HC (2000) Identification of the minimal functional unit in the low density lipoprotein receptor-related protein for binding the receptor-associated protein (RAP). A conserved acidic residue in the complement-type repeats is important for recognition of RAP. J Biol Chem 275(28):21017–21024
Anderson RB, Cianciolo GJ, Kennedy MN, Pizzo SV (2008) Alpha-2-macroglobulin binds CpG oligodeoxynucleotides and enhances their immunostimulatory properties by a receptor-dependent mechanism. J Leukoc Biol 83(2):381–392
Andus T, Gross V, Tran-Thi TA, Schreiber G, Nagashima M, Heinrich PC (1983) The biosynthesis of acute-phase proteins in primary cultures of rat hepatocytes. Eur J Biochem 133:561–571
Armstrong PB (2006) Proteases and protease inhibitors: a balance of activities in host-pathogen interaction. Immunobiology 211(4):263–281
Armstrong PB (2010) Role of apha-2-macroglobulin in the immune responses of invertebrates. Invertebr Surviv J 7:165–180
Armstrong PB, Quigley JP (1999) alpha-2-macroglobulin: an evolutionarily conserved arm of the innate immune system. Dev Comp Immunol 23:375–390
Armstrong PB, Levin J, Quigley JP (1984) Role of endogenous proteinase inhibitors in the regulation of the blood clotting system of the horseshoe crab, Limulus polyphemus. Thromb Haemost 52(2):117–120
Armstrong PB, Rossner MT, Quigley JP (1985) An alpha-2-macroglobulinlike activity in the blood of chelicerate and mandibulate arthropods. J Exp Zool 236(1):1–9
Armstrong PB, Mangel WF, Wall JS, Hainfield JF, Van Holde KE, Ikai A, Quigley JP (1991) Structure of alpha-2-macrolgobulin from the arthropod Limulus polyphemus. J Biol Chem 266(4):2526–2530
Arnold JN, Wallis R, Willis AC, Harvey DJ, Royle L, Dwek RA, Rudd PM, Sim RB (2006) Interaction of mannan binding lectin with alpha-2-macroglobulin via exposed oligomannose glycans: a conserved feature of the thiol ester protein family? J Biol Chem 281(11):6955–6963
Arolas JL, Goulas T, Pomerantsev AP, Leppla SH, Gomis-Ruth FX (2016) Structural basis for latency and function of immune inhibitor A metallopeptidase, a modulator of the Bacillus anthracis secretome. Structure 24(1):25–36
Banbula A, Chang LS, Beyer WF, Bohra CL, Cianciolo GJ, Pizzo SV (2005) The properties of rabbit alpha-1-macroglobulin upon activation are distinct from those of rabbit and human alpha-2-macroglobulin. J Biochem 138(5):527–537
Barcelona PF, Saragovi HU (2015) A pro-nerve growth factor (proNGF) and NGF binding protein, alpha-2-macroglobulin, differentially regulates p75 and TrkA receptors and is relevant to neurodegeneration ex vivo and in vivo. Mol Cell Biol 35(19):3396–3408
Barrett AJ, Starkey PM (1973) The interaction of alpha-2-macrolgobulin with proteinases. Biochem J 133:709–724
Barrett AJ, Brown MA, Sayers CA (1979) The electrophoretically ‘slow’ and ‘fast’ forms of the alpha-2-macroglobulin molecule. Biochem J 181:401–418
Baxter RHG, Chang C-I, Chelliah Y, Blandin S, Levashina EA, Deisenhofer J (2007) Structural basis for conserved complement factor-like function in the antimalarial protein TEP1. Proc Natl Acad Sci U S A 104(28):11615–11620
Bender RC, Bayne CJ (1996) Purification and characterisation of the tetrameric alpha-macroglobulin proteinase inhibitor from the gastropod mollusc Biomphalaria glabrata. Biochem J 316:893–900
Bhattacharjee G, Aspilin IR, Wu SM, Gawdi G, Pizzo SV (2000) The conformational-dependent interaction of alpha-2-macroglobulin with vascular endothelial growth factor: a novel mechanism of alpha-2-macroglobulin/growth factor binding. J Biol Chem 275(35):26806–26811
Birkenmeier G, Kämpfer I, Kratzsch J, Schellenberger W (1998) Human leptin forms complexes with alpha-2-macroglobulin which are recognized by the alpha-2-macroglobulin receptor/low density lipoprotein receptor-related protein. Eur J Endocrinol 139:224–230
Bloth B, Chesebro B, Svehag SE (1968) Ultrastructural studies of human and rabbit alpha-M-globulins. J Exp Med 127:749–762
Boisset N, Taveau J-C, Pochon F, Lamy J (1996) Similar architectures of native and transformed human alpha-2-macroglobulin suggest the transformation mechanism. J Biol Chem 271(42):25762–25769
Bonner JC, Goodell AL, Lasky JA, Hoffman (1991) Reversible binding of platelet-derived growth factor-AA, AB, and BB isoforms to a similar site on the “slow” and “fast” conformations of alpha-2-macroglobulin. J Biol Chem 267(18):12837–12844
Borth W (1992) alpha-2-Macroglobulin, a multifunctional bidning protein with targeting characteristics. FASEB J 6:3345–3353
Borth W, Scheer B, Urbansky A, Luger TA, Sottrup-Jensen L (1990) Binding of IL-1beta to alpha-2-macroglobulin and release by thioredoxin. J Immunol 145(11):3747–3754
Bowen ME, Gettins PG (1998) Bait region involvment in the dimer-dimer interface of human alpha-2-macroglobulin and in mediating gross conformational change. J Biol Chem 273(3):1825–1831
Brehme CS, Roman S, Shaffer J, Wolfert R (1999) Tartrate-resistant acid phosphatase forms complexes with alpha-2-macrolgobulin in serum. J Bone Miner Res 14:311–318
Brokx SJ, Ellison M, Locke T, Bottorff D, Frost L, Weiner JH (2004) Genome-wide analysis of lipoprotein expression in Escherichia coli MG1655. J Bacteriol 186(10):3254–3258
Budd A, Blandin S, Levashina E, Gibson JT (2004) Bacterial alpha-2-macroglobulins: colonization factors acquired by horizontal gene transfer from the metazoan genome? Genome Biol 5:R38
Buresova V, Hajdusek O, Franta Z, Sojka D, Kopacek P (2009) IrAM-An alpha-2-macroglobulin from the hard tick Ixodes ricinus: characterization and function in phagocytosis of a potential pathogen Chryseobacterium indologenes. Dev Comp Immunol 33(4):489–498
Bystrom J, Amin K, Bishop-Bailey D (2011) Analysing the eosinophil cationic protein-a clue to the function of the eosinophil granulocyte. Respir Res 12:10
Chu CT, Rubenstein DS, Enghild JJ, Pizzo SV (1991) Mechanism of insulin incorporation into alpha 2-macroglobulin: implications for the study of peptide and growth factor binding. Biochemistry 30(6):1551–1560
Cohn E, Strong L, Hughes W, Mulford D, Ashworth J, Melin M, Taylor H (1946) Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc 68(3):459–475
Cray C, Zaias J, Altman NH (2009) Acute phase response in animals: a review. Comp Med 59(6):517–526
Daly NL, Scanlon MJ, Djordjevic JT, Kroon PA, Smith R (1995) Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. Proc Natl Acad Sci U S A 92:6334–6338
De Wit CA, Weström BR (1987) Purification and characterisation of alpha-2-, alpha-2-beta-, and beta-macroglobulin inhibitors in the hedghog, Erinaceus europaeus: beta-Macroglobulin identified as the plasma antihemorrhagic factor. Toxicon 25(11):1209–1219
Dennis PA, Saksela O, Harpel P, Rifkin DB (1989) alpha-2-macroglobulin is a bidning protein for basic fibroblast growth factor. J Biol Chem 264(13):7210–7216
Doan N, Gettins PG (2007) Human alpha-2-macroglobulin is composed of multiple domains, as predicted by homology with complement component C3. Biochem J 407(1):23–30
Doan N, Gettins PG (2008) alpha-Macroglobulins are present in some gram-negative bacteria: characterization of the alpha-2-macroglobulin from Escherichia coli. J Biol Chem 283(42):28747–28756
Dodds AW, Ren XD, Willis AC, ASK L (1996) The reaction mechanism of the internal thioester in the human complement component C4. Nature 379:177–179
Dolmer K, Gettins PG (2006) Three complement-like repeats compose the complete alpha-2-macroglobulin binding site in the second ligand binding cluster of the low density lipoprotein receptor-related protein. J Biol Chem 281(45):34189–34196
Dolmer K, Jenner LB, Jacobsen L, Andersen GR, Koch TJ, Thirup S, Sottrup-Jensen L, Nyborg J (1995) Crystallisation and preliminary X-ray analysis of the receptor-binding domain of human and bovine alpha-2-macroglobulin. FEBS Lett 372:93–95
Dolmer K, Husted LB, Armstrong PB, Sottrup-Jensen L (1996) Localisation of the major reactive lysine residue involved in the self-crosslinking of proteinase-activated Limulus alpha-2-macroglobulin. FEBS Lett 393:37–40
Dolovich J, Wicher V (1971) The binding of Bacillus subtilis alkaline proteinases to alpha-2-macroglobulin. J Lab Clin Med 77:951–957
Drozdetskiy A, Cole C, Procter J, Barton GJ (2015) JPred4: a protein secondary structure prediction server. Nucleic Acids Res 43(W1):W389–W394
Du Y, Ni B, Glinn M, Dodel RC, Bales KR, Zhang Z, Hyslop PA, Paul SM (1997) alpha-2-Macroglobulin as a beta-amyloid peptide-binding plasma protein. J Neurochem 69:299–305
Dunn JT, Spiro RG (1967a) The alpha-2 macroglobulin of human plasma. Isolation and composition. J Biol Chem 242(23):5549–5555
Dunn JT, Spiro RG (1967b) The alpha-2-macroglobulin of human plasma. Studies on the carbohydrate units. J Biol Chem 242(23):5556–5563
Enghild JJ, Salvesen G, Thøgersen IB, Pizzo SV (1989) Proteinase binding and inhibition by the monomeric alpha-macroglobulin rat alpha-1-inhibitor-3. J Biol Chem 264(19):11428–11435
Enghild JJ, Thøgersen IB, Salvesen G, Fey GH, Figler NL, Gonias SL, Pizzo S (1990) Alpha-macroglobulin from Limulus polyphemus exhibits proteinase inhibitory activity and participates. Biochemistry 29(43):10070–10080
Eubanks LM, Stowe GN, De Lamo MS, Mayorov AV, Hixon MS, Janda KD (2011) Identification of alpha-2-macroglobulin as a major serum ghrelin esterase. Angew Chem Int Ed 50(45):10699–10702
Feige JJ, Negoescu A, Keramidas M, Souchelnitskiy S, Chambaz EM (1996) alpha-2-Macroglobulin: a binding protein for transforming growth factor-beta and various cytokines. Horm Res 43(3–5):227–232
Fredslund F, Jenner L, Husted LB, Nyborg J, Andersen GR, Sottrup-Jensen L (2006) The structure of bovine complement component 3 reveals the basis for thioester function. J Mol Biol 361(1):115–127
Fujito NT, Sugimoto S, Nonaka M (2010) Evolution of thioester-containing proteins revealed by cloning and characterization of their genes from a cnidarian sea anemone, Haliplanella lineate. Dev Comp Immunol 34(7):775–784
Fyfe CD, Grinter R, Josts I, Mosbahi K, Roszak AW, Cogdell RJ, Wall DM, Burchmore RJ, Byron O, Walker D (2015) Structure of protease-cleaved Escherichia coli alpha-2-macroglobulin reveals a putative mechanism of conformational activation for protease entrapment. Acta Crystallogr D Biol Crystallogr 71(Pt 7):1478–1486
Galliano MF, Toulza E, Gallinaro H, Jonca N, Ishida-Yamamoto A, Serre G, Guerrin M (2006) A novel protease inhibitor of the alpha-2-macroglobulin family expressed in the human epidermis. J Biol Chem 281(9):5780–5789
Garcia-Ferrer I, Arede P, Gomez-Blanco J, Luque D, Duquerroy S, Caston JR, Goulas T, Gomis-Ruth FX (2015) Structural and functional insights into Escherichia coli alpha-2-macroglobulin endopeptidase snap-trap inhibition. Proc Natl Acad Sci U S A 112(27):8290–8295
Gavish H, Bab I, Tartakovsky A, Chorev M, Mansur N, Greenberg Z, Namdar-Attar M, Muhlrad A (1997) Human alpha-2-macroglobulin is an osteogenic growth peptide-binding protein. Biochemistry 36(48):14883–14888
Gettins PG, Crews BC (1993) Epidermal growth factor binding to human alpha-2-macroglobulin. Implications for alpha-2-macroglobulin-growth factor interactions. Biochemistry 32(31):7916–7921
Gettins PG, K-h H, Crews BC (1995) alpha-2-Macroglobulin bait region variants. J Biol Chem 270(23):14160–14167
Ghetie MA, Uhr JW, Vitetta ES (1991) Covalent binding of human alpha-2-macroglobulin to deglycosylated ricin A chain and its immunotoxins. Cancer Res 51:1482–1487
Giroux E, Vargaftig BB (1978) Clostridio peptidase B inhibition by plasma macroglobulins and microbial antiproteases. Biochim et Biophys Acta – Enzymol 525(2):429–437
Gollas-Galvan T, Sotelo-Mundo RR, Yepiz-Plascencia G, Vargas-Requena C, Vargas-Albores F (2003) Purification and characterisation of alpha-2-macroglobulin from the white shrimp (Penaeus vannamei). Comp Biochem Physiol C Toxicol Pharmacol 134(4):431–438
Gonias SL, Pizzo SV (1983) Characterisation of functional human alpha-2-macroglobulin half-molecules isolated by limited reduction with dithiothreitol. Biochemistry 22:536–546
Gouin-Charnet A, Laune D, Granier C, Mani JC, Pau B, Mourad G, Argiles A (2000) alpha-2-Macroglobulin, the main serum antiprotease binds beta-2-microglobulin, the light chain of the class I major histocompatibility complex, which is involved in human disease. Clin Sci 98:427–433
Goulas T, Garcia-Ferrer I, Garcia-Pique S, Sottrup-Jensen L, Gomis-Ruth FX (2014) Crystallization and preliminary X-ray diffraction analysis of eukaryotic alpha-2-macroglobulin family members modified by methylamine, proteases and glycosidases. Mol Oral Microbiol 29(6):354–364
Gron H, Oike R, Potempa J, Travis J, Thogersen B, Enghild JJ, Pizzo SV (1997) The potential role of alpha-2-macroglobulin in the control of cysteine proteinases (gingipains) from Porphyromonas gingivalis. J Periodontal Res 32:61–68
Gunnarsson M, Jensen PE (1998) Binding of soluble myelin basic protein to various conformational forms of alpha-2-macrolgobulin. Arch Biochem Biophys 359:192–198
Hall M, Söderhall K (1994) Crayfish alpha-macroglobulin as a substrate for transglutaminases. Comp Biochem Physiol 108(1):65–72
Harpel PC (1970) Human plasma alpha-2-macroglobulin. An inhibitor of plasma kallikrein. J Exp Med 132(2):329–352
Hergenhahn H-G, Hall M, Söderhall K (1988) Purification and characterisation of an alpha-2-macroglobulin-like proteinase inhibitor from plasma of the crayfish Pacifastacus leniusculus. Biochem J 255:801–806
Hibbetts K, Hines B, Williams D (1999) An overview of proteinase inhibitors. J Vet Intern Med 13:302–308
Horvat RT, Clabaugh M, Duval-Jobe C, Parmely MJ (1989) Inactivation of human gamma interferon by Pseudomonas aeruginosa proteases: elastase augments the effects of alkaline protease despite the prsence of alpha-2-macroglobulin. Infect Immun 57(6):1668–1674
Huang W, Dolmer K, Liao X, Gettins PG (2000) NMR solution structure of the receptor binding domain of human alpha-2-macroglobulin. J Biol Chem 275(2):1089–1094
Husted LB, Sorensen ES, Armstrong PB, Quigley JP, Kristensen L, Sottrup-Jensen L (2002) Localization of carbohydrate attachment sites and disulfide bridges in Limulus alpha-2-macroglobulin. Evidence for two forms differing primarily in their bait region sequences. J Biol Chem 277(46):43698–43706
Ikai A, Osada T, Nishigai M (1988) Conformational changes of alpha-macroglobulin and ovomacroglobulin from the green turtle (Chelonia mydas japonica). J Biochem 103:218–224
Ikai A, Ookata K, Shimizu M, Nakamichi N, Ito M, Matsumura T (1999) A recombinant bait region mutant of human alpha-2-macroglobulin exhibiting an altered proteinase-inhibiting spectrum. Cytotechnology 31:53–60
Iwaki D, Kawabata S, Miura Y, Kato A, Armstrong PB, Quigley JP, Nielsen KL, Dolmer K, Sottrup-Jensen L, Iwanaga S (1996) Molecular cloning of Limulus alpha-2-macrolgobulin. Eur J Biochem 242:822–831
Janssen BJ, Huizinga EG, Raaijmakers HC, Roos A, Daha MR, Nilsson-Ekdahl K, Nilsson B, Gros P (2005) Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 437(7058):505–511
Jenner LB, Husted L, Thirup S, Sottrup-Jensen L, Nyborg J (1998) Crystal structure of the receptor-binding domain of alpha-2-macroglobulin. Structure 6(5):595–604
Jensen PE, Sottrup-Jensen L (1986) Primary structure of human alpha-2-macroglobulin. J Biol Chem 261(34):15863–15869
Jensen GA, Andersen OM, Bonvin AM, Bjerrum-Bohr I, Etzerodt M, Thogersen HC, O'Shea C, Poulsen FM, Kragelund BB (2006) Binding site structure of one LRP-RAP complex: implications for a common ligand-receptor binding motif. J Mol Biol 362(4):700–716
Kantyka T, Rawlings ND, Potempa J (2010) Prokaryote-derived protein inhibitors of peptidases: a sketchy occurrence and mostly unknown function. Biochimie 92(11):1644–1656
Kelwick R, Desanlis I, Wheeler GN, Edwards DR (2015) The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family. Genome Biol 16:113
Khan MH, Shibuya Y, Kambara T, Yamamoto T (1995) Role of alpha-2-macroglobulin and bacterial elastase in guinea-pig pseudomonal septic shock. Int J Exp Pathol 76:21–28
Kolodziej SJ, Schroeter JP, Strickland DK, Stoops JK (1996) The novel three-dimensional structure of native humna alpha-2-macroglobulin and comparisons with the structure of the methylamine derivative. J Struct Biol 116:366–376
Kolodziej SJ, Klueppelberg HU, Nolasco N, Ehses W, Strickland DK, Stoops JK (1998) Three-dimensional structure of the human plasmin alpha-2-macroglobulin complex. J Struct Biol 123(2):124–133
Kolodziej SJ, Wagenknecht T, Strickland DK, Stoops JK (2002) The three-dimensional structure of the human alpha-2-macroglobulin dimer reveals its structural organization in the tetrameric native and chymotrypsin alpha-2-macroglobulin complexes. J Biol Chem 277(31):28031–28037
Kopacek P, Weise C, Saravanan T, Vitova K, Grubhoffer L (2000) Characterization of an—alpha-macroglobulin-like glycoprotein isolated from the plasma of the soft tick Ornithodoros moubata. Eur J Biochem 267:465–467
Korkmaz B, Horwitz MS, Jenne DE, Gauthier F (2010) Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases. Pharmacol Rev 62(4):726–759
Kratzsch J, Selisko T, Birkenmeier G (1995) Identification of transformed alpha-2-macroglobulin as a growth hormone-binding protein in human blood. J Clin Endocrinol Metab 80(2):585–590
Kremers R, Bloemen S, Al Dieri R, Hemker CH, Karlaftis V, Attard C, de Laat B, Monagle P, Ignjatovic V (2013) alpha-2-Macroglobulin is a major determinant of a lower thrombin generation in infants and children compared to adults. Blood 122(21):2344–2344
Krimbou L, Tremblay M, Davignon J, Cohn JS (1998) Association of apolipoprotein E with alpha-2-macroglobulin in human plasma. J Lipid Res 39:2372–2386
Kurdowska A, Carr FK, Stevens MD, Baughman RP, Martin TR (1997) Studies on the interaction of IL-8 with human plasma alpha-2-macroglobulin. J Immunol 158(4):1930–1939
LaMarre J, Hayes AM, Wollenberg GK, Hussaini I, Hall SW, Gonias SL (1991a) An apha-2-macrolgobulin receptor-dependent mechanism for the plasma clearance of transforming growth factor-beta-1 in mice. J Clin Investig 87:39–44
LaMarre J, Wollenberg G, Gonias SL, Hayes AM (1991b) Cytokine binding and clearance properties of proteinase-activated alpha 2-macroglobulins. Lab Investig 65(1):3–14
Larquet E, Boisset N, Pochon F, Lamy J (1994) Architecture of native human alpha-2-macroglobulin studied by cryoelectron microscopy and three-dimensional reconstruction. J Struct Biol 113:87–98
Law ASK, Dodds AW (1997) The internal thioester and the covalent binding properties of the complement proteins C3 and C4. Protein Sci 6:263–274
Le BV, Williams M, Logarajah S, Baxter RH (2012) Molecular basis for genetic resistance of Anopheles gambiae to Plasmodium: structural analysis of TEP1 susceptible and resistant alleles. PLoS Pathog 8(10):e1002958
Li ZF, Wu XH, Engvall E (2004) Identification and characterization of CPAMD8, a novel member of the complement 3/alpha-2-macroglobulin family with a C-terminal Kazal domain. Genomics 83(6):1083–1093
Liebl DJ, Koo PH (1993) Comparative binding of neurotrophins (NT-3, CNTF, and NGF) and various cytokines to alpha-2-macroglobulin. Biochem Biophys Res Commun 193(3):1255–1261
Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK (2008) LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev 88(3):887–918
Lin M, Sutherland DR, Horsfall W, Totty N, Yeo E, Nayar R, Wu XF, Schuh AC (2002) Cell surface antigen CD109 is a novel member of the alpha-2-macroglobulin/C3, C4, C5 family of thioester-containing proteins. Blood 99(5):1683–1691
Lindroos PM, Coin PG, Osornio-Vargas AR, Bonner JC (1995) Interleukin 1 beta (IL-1 beta) and the IL-1 beta-alpha 2-macroglobulin complex upregulate the platelet-derived growth factor alpha-receptor on rat pulmonary fibroblasts. Am J Respir Cell Mol Biol 13(4):455–465
Liu Q, Ling TY, Shieh HS, Johnson FE, Huang JS, Huang SS (2001) Identification of the high affinity binding site in transforming growth factor-beta involved in complex formation with alpha 2-macroglobulin. Implications regarding the molecular mechanisms of complex formation between alpha 2-macroglobulin and growth factors, cytokines, and hormones. J Biol Chem 276(49):46212–46218
Lopez-Otin C, Bond JS (2008) Proteases: multifunctional enzymes in life and disease. J Biol Chem 283(45):30433–30437
Luan Y, Kong L, Howell DR, Ilalov K, Fajardo M, Bai XH, Di Cesare PE, Goldring MB, Abramson SB, Liu CJ (2008) Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin. Osteoarthr Cartil 16(11):1413–1420
Marrero A, Duquerroy S, Trapani S, Goulas T, Guevara T, Andersen GR, Navaza J, Sottrup-Jensen L, Gomis-Rüth XF (2012) The crystal structure of human alpha-2-macroglobulin reveals a unique molecular cage. Angew Chem Int Ed 51:3340–3344
Matsuda T, Hirano T, Nagasawa S, Kishimoto T (1989) Identification of alpha-2-macroglobulin as a carrier protein for IL6. J Immunol 142(1):148–152
McCaffrey TA, Falcone DJ, Brayton CF, Agarwal LA, Welt FGP, Weksler BB (1989) Transforming growth factor-beta activity is potentiated by heparin via dissociation of the transforming growth factor-beta/alpha-2-macroglobulin inactive complex. J Cell Biol 109:441–448
Merritt GC, Egerton JR, Loi JS (1971) Inhibition of Fusiformis nodosus protease and bovine trypsin by serum alpha-macroglobulin. J Comp Pathol 81(3):353
Mettenburg JM, Webb DJ, Gonias SL (2002) Distinct binding sites in the structure of alpha-2-macroglobulin mediate the interaction with beta-amyloid peptide and growth factors. J Biol Chem 277(15):13338–13345
Molla A, Matsumura Y, Yamamoto T, Okamura R, Maeda H (1987) Pathogenic capacity of proteases from Serratia marcescens and Pseudomonas aerginosa and their suppression by chicken egg white ovomacroglobulin. Infect Immun 55(10):2509–2517
Moncrief JS, Obiso R, Barroso L, Kling JJ, Wright RL, van Tassell RL, Lyerly DM, Wilkins TD (1995) The enterotoxin of Bacteroides fragilis is a metelloprotease. Infect Immun 63(1):175–181
Morrot A, Strickland DK, Higuchi M, Reis M, Pedrosa R, Scharfstein J (1997) Human T cell responses against the major cysteine proteinase (cruzipain) of Trypanosoma cruzi: role of the mutlifucntional alpha-2-macroglobulin receptor in antigen presentation by monocytes. Int Immunol 9(6):825–834
Müller H-P, Rantamäki LK (1995) Binding of native alpha-2-macroglobulin to human group G Streptococci. Infect Immun 63(8):2833–2839
Mutsuro J, Nakao M, Fujiki K, Yano T (2000) Multiple forms of alpha-2-macroglobulin from a bony fish, the common carp (Cyprinus carpio): striking sequence diversity in functional sites. Immunogenetics 51(10):847–855
Nagase H, Harris ED (1983) Ovostatin: a novel proteinase inhibitor from chicken egg white. J Exp Med 258(12):7481–7489
Nelson KE, Clayton RA, Gill SR, Gwinn ML, Dodson RJ, Haft DH, Hickey EK, Peterson JD, Nelson WC, Ketchum KA, McDonald L, Utterback TR, Malek JA, Linher KD, Garrett MM, Stewart AM, Cotton MD, Pratt MS, Phillips CA, Richardson D, Heidelberg J, Sutton GG, Fleischmann RD, Eisen JA, White O, Salzberg SL, Smith HO, Venter JC, Fraser CM (1999) Evidence for lateral gene transfer between archaea and bacteria from genome sequence of Thermotoga maritima. Nature 399:323–329
Neves D, Estrozi LF, Job V, Gabel F, Schoehn G, Dessen A (2012) Conformational states of a bacterial alpha-2-macroglobulin resemble those of human complement C3. PLoS One 7(4):e35384
Nielsen KL, Sottrup-Jensen L, Nagase H, Thøgersen HC, Etzerodt M (1994) Amino acid sequence of hen ovomacroglobulin (ovostatin) deduced from cloned cDNA. DNA Seq 5(2):111–119
Nielsen KL, Holtet TL, Etzerodt M, Moestrup SK, Gliemann J, Sottrup-Jensen L, Thogersen HC (1996) Identification of residues in alpha-macroglobulin important for binding to the alpha-2-macrolgobulin receptor/low density lipoprotein receptor relatef protein. J Biol Chem 271(22):12909–12912
Niemuller CA, Randall KJ, Webb DJ, Gonias SL, LaMarre J (1995) Alpha-2-macroglobulin conformation determines binding affinity for activin A and plasma clearance of activin A/alpha-2-macroglobulin complex. Endocrinology 136(12):5343–5349
Nonaka M (2011) The complement C3 protein family in invertebrates. Invertebr Surviv J 8:21–32
Nothaft H, Szymanski CM (2010) Protein glycosylation in bacteria: sweeter than ever. Nat Rev Microbiol 8(11):765–778
Paiva MM, Soeiro MN, Barbosa HS, Meirelles MN, Delain E, Araujo-Jorge TC (2010) Glycosylation patterns of human alpha-2-macroglobulin: analysis of lectin binding by electron microscopy. Micron 41(6):666–673
Panyutich A, Ganz T (1991) Activated alpha-2-macroglobulin is a principal defensin-binding protein. Am J Respir Cell Mol Biol 5:101–106
Perazzolo LM, Bachere E, Rosa RD, Goncalves P, Andreatta ER, Daffre S, Barracco MA (2011) alpha-2-Macroglobulin from an Atlantic shrimp: biochemical characterization, sub-cellular localization and gene expression upon fungal challenge. Fish Shellfish Immunol 31(6):938–943
Peslova G, Petrak J, Kuzelova K, Hrdy I, Halada P, Kuchel PW, Soe-Lin S, Ponka P, Sutak R, Becker E, Huang ML, Suryo Rahmanto Y, Richardson DR, Vyoral D (2009) Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood. Blood 113(24):6225–6236
Petersen CG, Venge P (1987) Interaction and complex-formation between the eosinophil cationic protein and alpha-2-macroglobulin. Biochem J 245:781–787
Petersen LC, Elm T, Ezban M, Krogh TN, Karpf DM, Steino A, Olsen EH, Sorensen BB (2009) Plasma elimination kinetics for factor VII are independent of its activation to factor VIIa and complex formation with plasma inhibitors. Thromb Haemost 101(5):795–990
Phillips DJ, McFarlane JR, Hearn MTW, Krester DM (1997) Inhibin, activin and follistatin bind preferentially to the transformed species of alpha-2-macroglobulin. J Endocrinol 155:65–71
Pochon F, Barrey M, Delain E (1989) Dissociation of alpha-2-macroglobulin into functional half-molecules by mild acid treatment. Biochim Biophys Acta 996:132–138
Pugsley A (1993) The complete general secretory pathway in Gram-negative bacteria. Microbiol Rev 57(1):50–108
Qazi U, Gettins PG, Strickland DK, Stoops JK (1999) Structural details of proteinase entrapment by human alpha-2-macroglobulin emerge from three-dimensional reconstructions of Fab labeled native, half-transformed, and transformed molecules. J Biol Chem 274(12):8137–8142
Qazi U, Kolodziej SJ, Gettins PG, Stoops JK (2000) The structure of the C949S mutant human alpha-2-macroglobulin demonstrates the critical role of the internal thiol esters in its proteinase-entrapping structural transformation. J Struct Biol 131(1):19–26
Quigley JP, Ikai A, Arakawa H, Osada T, Armstrong PB (1991) Reaction of proteinases with alpha-2-macroglobulin from the american horseshoe crab, Limulus. J Biol Chem 266(26):19426–19431
Rasmussen M, Müller H-P, Björck L (1999) Protein GRAB of Streptococcus pyogenes regulates proteolysis at the bacterial surface by bnding alpha-2-macroglobulin. J Biol Chem 274(22):15336–15344
Raymond WW, Su S, Makarova A, Wilson TM, Carter MC, Metcalfe DD, Caughey GH (2009) alpha-2-Macroglobulin capture allows detection of mast cell chymase in serum and creates a reservoir of angiotensin II-generating activity. J Immunol 182(9):5770–5777
Robert-Genthon M, Casabona MG, Neves D, Coute Y, Ciceron F, Elsen S, Dessen A, Attree I (2013) Unique features of a Pseudomonas aeruginosa alpha-2-macroglobulin homolog. MBio 4(4):e00309–e00313
Ronne H, Anundi H, Rask L, Peterson PA (1979) Nerve growth factor binds to serum alpha-2-macroglobulin. Biochem Biophys Res Commun 87(1):330–336
Rubenstein DS, Thogersen IB, Pizzo SV, Enghild JJ (1993) Identification of monomeric alpha-macroglobulin proteinase inhibitors in birds, reptiles, amphibians and mammals, and purification and characterisation of a monomeric alpha-macroglobulin proteinase inhibitor from the American bullfrog Rana catesbiana. Biochem J 290:85–89
Rudenko G, Henderson K, Ichtchenko K, Brown MS, Goldstein JL, Deisenhofer J (2002) Structure of the LDL receptor extreacellualar doamin at endosomal pH. Science 298:2353–2358
Rudloe A (1979) Limulus polyphemus: a review of the ecologically significant literature. In: Cohen E (ed) Biomedical applications of the horse shoe crab. Alan R. Liss, New York, pp 27–35
Sahu A, Lambris JD (2001) Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunol Rev 180:35–48
Sand O, Folkersen J, Westergaard JG, Sottrup-Jensen L (1985) Characterisation in human pregnancy zone protein. Comparison with human alpha-2-macrolgobulin. J Biol Chem 260(29):15723–15735
Schaller J, Gerber SS (2011) The plasmin-antiplasmin system: structural and functional aspects. Cell Mol Life Sci 68(5):785–801
Scharfstein J (2006) Parasite cysteine proteinase interactions with alpha-2-macroglobulin or kininogens: differential pathways modulating inflammation and innate immunity in infection by pathogenic trypanosomatids. Immunobiology 211(1–2):117–125
Schroeter JP, Kolodziej SJ, Wagenknecht T, Bretaudiere J-P, Tapon-Bretaudiere J, Strickland DK, Stoops JK (1992) Three-dimensional structures of the human alpha-2-macroglobulin-methylamine and chymotrypsin complexes. J Struct Biol 109:235–247
Seydel A, Gounon P, Pugsley A (1999) Testing the ‘+2 rule’ for lipoprotein sorting in the Escherichia coli cell envelope with a new genetic selection. Mol Microbiol 34(4):810–821
Shanbhag VP, Stigbrand T, Jensen PE (1996) The conformational state of human alpha-2-macroglobulin influences its dissociation into half-molecules by sodium thiocyanate. Arch Biochem Biophys 333(1):35–41
Soker S, Svahn CM, Neufeld G (1993) Vascular endothelial growth factor is inactivated by binding to alpha-2-macroglobulin and the binding is inhibited by heparin. J Biol Chem 268(11):7685–7691
Sottrup-Jensen L (1989) alpha-Macroglobulin: structure, shape, and mechanism of proteinase complex formation. J Biol Chem 264(20):11539–11542
Sottrup-Jensen L (1994) Role of internal thiol esters in the alpha-macroglobulin-proteinase binding mechanism. Ann N Y Acad Sci 737:172–187
Sottrup-Jensen L, Folkersen J, Kristensen L, Tack BF (1984a) Partial primary structure of human pregnancy zone protein: extensive sequence homology with human alpha-2-macroglobulin. Proc Natl Acad Sci U S A 81:7353–7357
Sottrup-Jensen L, Stepanik TM, Kristensen T, Wierzbicki DM, Jones CM, Lonbland PB, Magnusson S, Petersen TE (1984b) Primary structure of human alpha-2-macroglobulin. V. The complete structure. J Biol Chem 259(13):8318–8327
Sottrup-Jensen L, Stepanik TM, Kristensen T, Lonbland PB, Jones CM, Wierzbicki DM, Magnusson S, Domdey H, Wetsel RA, Lundwall A, Tack BF, Fey GH (1985) Common evolutionary origin of alpha-2-macroglobulin and complement components C3 and C4. Proc Natl Acad Sci U S A 82:9–13
Sottrup-Jensen L, Sand O, Kristensen T, Fey GH (1989) The alpha-macroglobulin bait region. Sequence diversity and localisation of cleavage sites for proteinases in five mammalian alpha-macroglobulins. J Biol Chem 264(27):15781–15789
Spycher SE, Arya S, Isenman DE, Painter RH (1987) A functional, thioester-containing alpha-2-macroglobulin homologue isolated from the hemolymph of the american lobster (Homarus americanus). J Biol Chem 262:14606–14611
Starkey PM, Barrett AJ (1982) Evolution of alpha-2-macroglobulin. The demonstration in a variety of vertebrate species of a protein resembling human alpha-2-macroglobulin. Biochem J 205:91–95
Stöcker W, Breit S, Sottrup-Jensen L, Zwilling R (1991) alpha-2-Macroglobulin from the haemolymph of the freshwater crayfish Astacus astacus. Comp Biochem Physiol 98B(4):501–509
Suda SA, Dolmer K, Gettins PG (1997) Critical role of asparagine 1065 of human alpha-2-macroglobulin in formation and reactivity of the thiol ester. J Biol Chem 272(49):31107–31112
Sunderic M, Malenkovic V, Nedic O (2015) Complexes between insulin-like growth factor binding proteins and alpha-2-macroglobulin in patients with tumor. Exp Mol Pathol 98(2):173–177
Swarnakar S, Asokan R, Quigley JP, Armstrong PB (2000) Binding of alpha-2-macrolgobulin and limulin: regulation of the plasma haemolytic system of the American horseshoe crab, Limulus. Biochem J 347:679–685
Thøgersen HC, Salvesen G, Brucato FH, Pizzo SV, Enghild JJ (1992) Purification and characterisation of an alpha-macroglobulin proteinase inhibitor from the mollusc Octopus vulgaris. Biochem J 285:521–527
Tortorella MD, Arner EC, Hills R, Easton A, Korte-Sarfaty J, Fok K, Wittwer AJ, Liu RQ, Malfait AM (2004) alpha-2-Macroglobulin is a novel substrate for ADAMTS-4 and ADAMTS-5 and represents an endogenous inhibitor of these enzymes. J Biol Chem 279(17):17554–17561
Tunstall AM, Merriman JML, Milne I, James K (1975) Normal and pathological serum levels of alpha-2-macroglobulins in men and mice. J Clin Pathol 28:133–139
Valnickova Z, Thøgersen IB, Christensen S, Chu CT, Pizzo SV, Enghild JJ (1996) Activate human plasma carboxypeptidase B is retained in the blood by binding to alpha-2-macroglobulin and pregnancy zone protein. J Biol Chem 271(22):12937–12943
Van Jaarsveld F, Naudé RJ, Oelofsen RJ, Travis J (1994) The isolation and partial characterisation of alpha-2-macroglobulin from the serum of the ostrich (Struthio camelus). Int J Biochem 26(1):97–110
Van Rompaey L, Proost P, Van den Berghe H, Marynen P (1995) Design of a new protease inhibitor by the manipulation of the bait region of alpha-2-macroglobulin: inhibition of the tobacco etch virus protease by mutant alpha-2-macroglobulin. Biochem J 312:191–195
Vanhoorelbeke K, Goossens A, Gielens C, Preaux G (1993) An alpha-2-macroglobulin-like proteinase inhibitor inthe haemolymph of the Decabrachia cephalopod Sepia officinalis. Arch Int Physiol Biochim Biophys 102:B25
Vilella E, Bengtsson-Olivecrona G, Stigbrand T, Jensen PE (1994) Binding of lipoprotein lipase to alpha-2-macroglobulin. Biochem J 300:443–448
Wacker M, Linton D, Hitchen PG, Nita-Lazar M, Haslam SM, North SJ, Panico M, Morris HR, Dell A, Wren BW, Aebi M (2002) N-linked glycosylation in Campylobacter jejuni and its functional transfer into E. coli. Science 298:1790–1793
Walter M, Sutton RM, Schechter NM (1999) Highly efficient inhibition of human chymase by alpha-2-macroglobulin. Arch Biochem Biophys 368(2):276–284
Wang S, Wei X, Zhou J, Zhang J, Li K, Chen Q, Terek R, Fleming BC, Goldring MB, Ehrlich MG, Zhang G, Wei L (2014) Identification of alpha-2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis. Arthritis Rheum 66(7):1843–1853
Webb DJ, Wen J, Karns LR, Kurilla MG, Gonias SL (1998) Localisation of the binding site for the transforming growth factor-beta in human alpha-2-macroglobulin to a 20 kDa peptide that also contains the bait region. J Biol Chem 273(21):13339–13346
Werb Z, Burleigh MC, Barrett AJ, Starkey PM (1973) The interaction of alpha-2-macroglobulin with proteinases. Binding and inhibitions of mammalian collagenases and other metal proteinases. Biochem J 139:359–368
Wolf BB, Gonias SL (1994) Neurotrophin binding to human alpha-2-macroglobulin under apparent equilibrium conditions. Biochemistry 33(37):11270–11277
Wollenberg G, LaMarre J, Rosendal S, Gonias SL, Hayes AM (1991) Binding of tumor necrosis factor alpha to activated forms of human plasma alpha-2-macroglobulin. Am J Pathol 138(2):265–272
Wong SG, Dessen A (2014) Structure of a bacterial alpha-2-macroglobulin reveals mimicry of eukaryotic innate immunity. Nat Commun 5:4917
Wyatt AR, Constantinescu P, Ecroyd H, Dobson CM, Wilson MR, Kumita JR, Yerbury JJ (2013) Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms. FEBS Lett 587(5):398–403
Wyatt AR, Kumita JR, Mifsud RW, Gooden CA, Wilson MR, Dobson CM (2014) Hypochlorite-induced structural modifications enhance the chaperone activity of human alpha-2-macroglobulin. Proc Natl Acad Sci U S A 111(20):E2081–E2090
Xiao T, Decamp DL, Sprang SR (2000) Structure of a rat alpha-1-macroglobulin receptor-binding domain dimer. Protein Sci 9:1889–1897
Yigzaw Y, Gielens C, Préaux G (2001) Isolation and characterisation of an alpha-macroglobulin from the gastropod mollusc Helix pomatia with tetrameric structure and preserved activity after methylamine treatment. Biochim Biophys Acta 1545:104–113
Acknowledgements
This study was funded in part by grants from European, Spanish, and Catalan agencies (FP7-PEOPLE-2011-ITN-290246 “RAPID”; FP7-HEALTH-2012-306029-2 “TRIGGER”; BFU2015-64487-R; BIO2013-49320-EXP; MDM-2014-0435; 2014SGR9). TG acknowledges “Juan de la Cierva” research contracts (JCI-2012-13573) from the Spanish Ministry for Economy and Competitiveness. The Structural Biology Unit of IBMB is a “María de Maeztu” Unit of Excellence of the Ministry of Economy and Competitiveness.
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Garcia-Ferrer, I., Marrero, A., Gomis-Rüth, F.X., Goulas, T. (2017). α2-Macroglobulins: Structure and Function. In: Harris, J., Marles-Wright, J. (eds) Macromolecular Protein Complexes. Subcellular Biochemistry, vol 83. Springer, Cham. https://doi.org/10.1007/978-3-319-46503-6_6
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