Summary: A-macroglobulin TED domain
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Alpha-2-Macroglobulin Edit Wikipedia article
alpha-2-Macroglobulin (α2M) 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.
Alpha 2 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. Alpha-2-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 alpha-2-macroglobulin. The concentration of alpha-2-macroglobulin rises 10-fold or more in the nephrotic syndrome when other lower molecular weight proteins are lost in the urine. The loss of alpha-2-macroglobulin into urine is prevented by its large size. The net result is that alpha-2-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
Human alpha-2-macroglobulin is composed of four identical subunits bound together by -S-S- bonds.[5][6] In addition to tetrameric forms of alpha-2-macroglobulin, dimeric, and more recently monomeric aM protease inhibitors have been identified.[7][8]
Each monomer of human alpha-2-macroglobulin is composed of several functional domains, including macroglobulin domains, a thiol ester-containing domain and a receptor-binding domain.[9] Overall, alpha-2-Macroglobulin is the largest major nonimmunoglobulin protein in human plasma.
The amino acid sequence of alpha-2-macroglobulin has been shown to be 71% the same as that of the Pregnancy zone protein.[10]
Function
The alpha-macroglobulin (aM) family of proteins includes protease inhibitors,[11] typified by the human tetrameric alpha-2-macroglobulin (a2M); they belong to the MEROPS proteinase inhibitor family I39, clan IL. These protease inhibitors share several defining properties, which include (i) the ability to inhibit proteases from all catalytic classes, (ii) the presence of a 'bait region' (aka. 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, (iii) a similar protease inhibitory mechanism and (iv) 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 (i) the h-cysteinyl-g-glutamyl thiol ester becomes highly reactive and (ii) 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]
alpha-2-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] Alpha-2-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.
alpha-2-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] 10-15% of copper in human plasma is chelated by alpha-2-macroglobulin.[17]
Disease
alpha-2-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, alpha-2-macroglobulin is retained in the bloodstream. Increased production of all proteins means alpha-2-macroglobulin concentration increases. This increase has little adverse effect on the health, but is used as a diagnostic clue. Longstanding chronic renal failure can lead to amyloid by alpha-2-macroglobulin (see main article: amyloid).
A common variant (29.5%) (polymorphism) of alpha-2-macroglobulin leads to increased risk of Alzheimer's disease.[19][20]
alpha-2-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
- ^ 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.
- ^ 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. 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.
- ^ 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 reactionâ€. Biochimica et Biophysica Acta. 1088(1): 95-103
- ^ Sottrup-Jensen L (July 1989). "Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation". J. Biol. Chem. 264 (20): 11539–42. 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. 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. 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. 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.
- ^ 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.
- ^ 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.
- McPherson & Pincus: Henry's Clinical Diagnosis and Management by Laboratory Methods, 21st ed.
- Firestein: Kelley's Textbook of Rheumatology, 8th edition.
External links
- The MEROPS online database for peptidases and their inhibitors: I39.001
- alpha+2-Macroglobulin at the US 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.
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A-macroglobulin TED domain Provide feedback
This entry corresponds to the TED domain of the complement components such as C3, C4 and C5. This domain contains a short highly conserved region of proteinase-binding alpha-macro-globulins contains the cysteine and a glutamine of a thiol-ester bond that is cleaved at the moment of proteinase binding, and mediates the covalent binding of the alpha-macro-globulin to the proteinase. The GCGEQ motif is highly conserved.
Literature references
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Huang W, Dolmer K, Liao X, Gettins PG; , J Biol Chem 2000;275:1089-1094.: NMR solution structure of the receptor binding domain of human alpha(2)-macroglobulin. PUBMED:10625650 EPMC:10625650
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Xiao T, DeCamp DL, Spran SR; , Protein Sci 2000;9:1889-1897.: Structure of a rat alpha 1-macroglobulin receptor-binding domain dimer. PUBMED:11106161 EPMC:11106161
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Szakonyi G, Guthridge JM, Li D, Young K, Holers VM, Chen XS; , Science 2001;292:1725-1728.: Structure of complement receptor 2 in complex with its C3d ligand. PUBMED:11387479 EPMC:11387479
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Zanotti G, Bassetto A, Battistutta R, Folli C, Arcidiaco P, Stoppini M, Berni R; , Biochim Biophys Acta 2000;1478:232-238.: Structure at 1.44 A resolution of an N-terminally truncated form of the rat serum complement C3d fragment. PUBMED:10825534 EPMC:10825534
Internal database links
| SCOOP: | A2M_recep Prenyltrans SQHop_cyclase_C SQHop_cyclase_N |
| Similarity to PfamA using HHSearch: | SQHop_cyclase_C SQHop_cyclase_C |
External database links
| PROSITE: | PDOC00440 |
This tab holds annotation information from the InterPro database.
InterPro entry IPR011626
This entry corresponds to the TED domain of the complement components such as C3, C4 and C5. This domain contains a short highly conserved region of proteinase-binding alpha-macro-globulins contains the cysteine and a glutamine of a thiol-ester bond that is cleaved at the moment of proteinase binding, and mediates the covalent binding of the alpha-macro-globulin to the proteinase. The GCGEQ motif is highly conserved [ PUBMED:10625650 , PUBMED:11106161 , PUBMED:11387479 , PUBMED:10825534 ].
Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
| Cellular component | extracellular space (GO:0005615) |
Domain organisation
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Pfam Clan
This family is a member of clan 6_Hairpin (CL0059), which has the following description:
This Clan includes CAZy clans GH-L, GH-M and GH-G. The members of this clan share a common structure composed of 6 helical hairpins. Most members of this superfamily are glycosyl hydrolase enzymes.
The clan contains the following 29 members:
Bac_rhamnosid6H C5-epim_C Cobalamin_bind DUF608 GDE_C GlcNAc_2-epim Glyco_hydro81C Glyco_hydro_100 Glyco_hydro_125 Glyco_hydro_127 Glyco_hydro_15 Glyco_hydro_36 Glyco_hydro_47 Glyco_hydro_48 Glyco_hydro_63 Glyco_hydro_65m Glyco_hydro_76 Glyco_hydro_8 Glyco_hydro_88 Glyco_hydro_9 Glycoamylase LANC_like Ldi Pec_lyase Prenyltrans SQHop_cyclase_C SQHop_cyclase_N TED_complement TrehalaseAlignments
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...
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| Seed (21) |
Full (6726) |
Representative proteomes | UniProt (19692) |
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| RP15 (1068) |
RP35 (2719) |
RP55 (6212) |
RP75 (8510) |
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| PP/heatmap | 1 | ||||||
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| Seed (21) |
Full (6726) |
Representative proteomes | UniProt (19692) |
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|---|---|---|---|---|---|---|---|
| RP15 (1068) |
RP35 (2719) |
RP55 (6212) |
RP75 (8510) |
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| Raw Stockholm | |||||||
| Gzipped | |||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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Trees
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | Prosite |
| Previous IDs: | A2M3; A2M_comp; |
| Type: | Repeat |
| Sequence Ontology: | SO:0001068 |
| Author: |
Studholme DJ  , Sammut SJ , Bateman A
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| Number in seed: | 21 |
| Number in full: | 6726 |
| Average length of the domain: | 243.90 aa |
| Average identity of full alignment: | 28 % |
| Average coverage of the sequence by the domain: | 18.63 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 311 | ||||||||||||
| Family (HMM) version: | 16 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Structures
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the TED_complement domain has been found. There are 137 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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