Summary: MG2 domain
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This is the Wikipedia entry entitled "Alpha-2-Macroglobulin". More...
Alpha-2-Macroglobulin
| alpha-2-macroglobulin | |
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| Crystal structure of alpha-2-macroglobulin. Rendered from PDB 2P9R. | |
| Identifiers | |
| Symbol | A2M |
| Entrez | 2 |
| HUGO | 7 |
| OMIM | 103950 |
| RefSeq | NM_000014 |
| UniProt | P01023 |
| Other data | |
| Locus | Chr. 12 p13.31 |
| Identifiers | |||||||||
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| Symbol | A2M | ||||||||
| Pfam | PF00207 | ||||||||
| Pfam clan | CL0011 | ||||||||
| InterPro | IPR001599 | ||||||||
| PROSITE | PDOC00440 | ||||||||
| SCOP | 1c3d | ||||||||
| SUPERFAMILY | 1c3d | ||||||||
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| n-terminally truncated c3dg fragment | |||||||||
| Identifiers | |||||||||
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| Symbol | A2M_comp | ||||||||
| Pfam | PF07678 | ||||||||
| Pfam clan | CL0059 | ||||||||
| InterPro | IPR011626 | ||||||||
| PROSITE | PDOC00440 | ||||||||
| SCOP | 1bv8 | ||||||||
| SUPERFAMILY | 1bv8 | ||||||||
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| Identifiers | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Symbol | A2M_N | ||||||||
| Pfam | PF01835 | ||||||||
| Pfam clan | CL0159 | ||||||||
| InterPro | IPR002890 | ||||||||
| SCOP | 2a73 | ||||||||
| SUPERFAMILY | 2a73 | ||||||||
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| Identifiers | |||||||||
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| Symbol | A2M_N_2 | ||||||||
| Pfam | PF07703 | ||||||||
| InterPro | IPR011625 | ||||||||
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| receptor domain from alpha-2-macroglobulin | |||||||||
| Identifiers | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Symbol | A2M_recep | ||||||||
| Pfam | PF07677 | ||||||||
| InterPro | IPR009048 | ||||||||
| PROSITE | PDOC00440 | ||||||||
| SCOP | 1bv8 | ||||||||
| SUPERFAMILY | 1bv8 | ||||||||
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alpha-2-Macroglobulin, also known as α2-macroglobulin and abbreviated as α2M and A2M, is a large plasma protein found in the blood. It is produced by the liver, and is a major component of the alpha-2 band in protein electrophoresis.
Alpha 2-Macroglobulin is the largest major nonimmunoglobulin protein in plasma. The alpha 2-macroglobulin molecule is synthesized mainly in liver, but also locally by macrophages, fibroblasts, and adrenocortical cells.
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.
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[edit] Structure
Human alpha-2-macroglobulin is composed of four identical subunits bound together by -S-S- bonds.[1][2] In addition to tetrameric forms of alpha-2-macroglobulin, dimeric, and more recently monomeric aM protease inhibitors have been identified.[3][4]
Each monomer of Human alpha-2-macroglobulin is composed of many functional domains, including macroglobulin domains, a thiol ester-containing domain and a receptor-binding domain.[5]
[edit] Function
The alpha-macroglobulin (aM) family of proteins includes protease inhibitors,[6] 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 (i) the ability to inhibit proteases from all catalytic classes, (ii) the presence of a 'bait region' 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.[7] 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 [8] (RBD). RBD exposure allows the aM protease complex to bind to clearance receptors and be removed from circulation.[9] Tetrameric, dimeric, and, more recently, monomeric aM protease inhibitors have been identified.[3][4]
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.[10]
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.
[edit] Disease
Alpha-2-macroglobulin levels are increased 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. Longstanding chronic renal failure can lead to amyloid by alpha-2-macroglobulin (see main article: amyloid).
A common variant (29.5%) (polymorphism) of α2-macroglobulin leads to increased risk of Alzheimer's disease,[11][12]
α-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.
[edit] References
- ^ 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. 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. . PMID 17608619. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17608619.
- ^ 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. . PMID 7693593. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=281280.
- ^ 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.
[edit] External links
- The MEROPS online database for peptidases and their inhibitors: I39.001
- MeSH alpha+2-Macroglobulin
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This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
MG2 domain
This is the MG2 (macroglobulin) domain of alpha-2-macroglobulin [1].
Literature references
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Janssen BJ, Huizinga EG, Raaijmakers HC, Roos A, Daha MR, Nilsson-Ekdahl K, Nilsson B, Gros P;, Nature. 2005;437:505-511.: Structures of complement component C3 provide insights into the function and evolution of immunity. PUBMED:16177781
Clan
This family is a member of clan E-set (CL0159), which has a total of 60 members.
External database links
| PANDIT: | PF01835 |
| Pseudofam: | PF01835 |
| SCOP: | 2a73 |
| SYSTERS: | A2M_N |
This tab holds annotation information from the InterPro database.
InterPro entry IPR002890
The proteinase-binding alpha-macroglobulins (A2M) [PUBMED:2473064] are large glycoproteins found in the plasma of vertebrates, in the hemolymph of some invertebrates and in reptilian and avian egg white. A2M-like proteins are able to inhibit all four classes of proteinases by a 'trapping' mechanism. They have a peptide stretch, called the 'bait region', which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein, thus trapping the proteinase. The entrapped enzyme remains active against low molecular weight substrates, whilst its activity toward larger substrates is greatly reduced, due to steric hindrance. Following cleavage in the bait region, a thiol ester bond, formed between the side chains of a cysteine and a glutamine, is cleaved and mediates the covalent binding of the A2M-like protein to the proteinase. This family includes the N-terminal region of the alpha-2-macroglobulin family.
The inhibitor domains belong to MEROPS inhibitor family I39.
Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
| Molecular function | endopeptidase inhibitor activity (GO:0004866) |
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Pfam Clan
This family is a member of clan E-set (CL0159), which contains the following 60 members:
A2M_N Alpha_adaptinC2 Big_1 Big_2 Big_3 Big_3_2 Big_3_3 Big_3_4 Big_4 Big_5 BiPBP_C Bre5 BsuPI Cadherin Cadherin-like Cadherin_2 Cadherin_pro CARDB CHB_HEX_C CHB_HEX_C_1 ChitinaseA_N CHU_C CopC DUF1034 DUF11 DUF1927 DUF1973 DUF2271 DUF4165 DUF916 EpoR_lig-bind Filamin FlgD_ig fn3 Fn3_assoc He_PIG HYR IFNGR1 IL6Ra-bind Integrin_alpha2 Interfer-bind Invasin_D3 MG1 Mo-co_dimer Neurexophilin NPCBM_assoc PbH1 Pili_assembly_N PKD PPC REJ Rib SoxZ SWM_repeat T2SS-T3SS_pil_N TIG Tissue_fac Transglut_C TRAP_beta Y_Y_YAlignments
There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...
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The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.
You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.
External links
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
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Trees
This page displays the phylogenetic tree for this family. 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 or full alignments.
Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.
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: | Pubmed:16177781 |
| Previous IDs: | none |
| Type: | Domain |
| Author: | Bateman A |
| Number in seed: | 175 |
| Number in full: | 1731 |
| Average length of the domain: | 96.60 aa |
| Average identity of full alignment: | 22 % |
| Average coverage of the sequence by the domain: | 6.18 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 15929002 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 99 | ||||||||||||
| Family (HMM) version: | 14 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Colour assignments
Archea
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Eukaryota
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Viruses
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Unclassified
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Unclassified sequence
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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 A2M_N domain has been found. There are 32 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 seqence.
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