Full text data of A2M
A2M
(CPAMD5)
[Confidence: low (only semi-automatic identification from reviews)]
Alpha-2-macroglobulin; Alpha-2-M (C3 and PZP-like alpha-2-macroglobulin domain-containing protein 5; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Alpha-2-macroglobulin; Alpha-2-M (C3 and PZP-like alpha-2-macroglobulin domain-containing protein 5; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P01023
ID A2MG_HUMAN Reviewed; 1474 AA.
AC P01023; Q13677; Q59F47; Q5QTS0; Q68DN2; Q6PIY3; Q6PN97;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-OCT-2010, sequence version 3.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=Alpha-2-macroglobulin;
DE Short=Alpha-2-M;
DE AltName: Full=C3 and PZP-like alpha-2-macroglobulin domain-containing protein 5;
DE Flags: Precursor;
GN Name=A2M; Synonyms=CPAMD5; ORFNames=FWP007;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS ASP-639 AND VAL-1000.
RX PubMed=2581245; DOI=10.1073/pnas.82.8.2282;
RA Kan C.-C., Solomon E., Belt K.T., Chain A.C., Hiorns L.R., Fey G.H.;
RT "Nucleotide sequence of cDNA encoding human alpha 2-macroglobulin and
RT assignment of the chromosomal locus.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:2282-2286(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS ASP-639 AND VAL-1000.
RC TISSUE=Prostate;
RX PubMed=15611997; DOI=10.1002/pros.20183;
RA Lin V.K., Wang S.-Y., Boetticher N.C., Vazquez D.V., Saboorian H.,
RA McConnell J.D., Roehrborn C.G.;
RT "Alpha(2) macroglobulin, a PSA-binding protein, is expressed in human
RT prostate stroma.";
RL Prostate 63:299-308(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASP-639.
RC TISSUE=Spleen;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ASP-639 AND
RP VAL-1000.
RC TISSUE=Liver;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ASP-639 AND
RP VAL-1000.
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-29.
RC TISSUE=Placenta;
RX PubMed=1374237; DOI=10.1016/0006-291X(92)90631-T;
RA Matthijs G., Devriendt K., Cassiman J.-J., van den Berghe H.,
RA Marynen P.;
RT "Structure of the human alpha-2 macroglobulin gene and its promotor.";
RL Biochem. Biophys. Res. Commun. 184:596-603(1992).
RN [8]
RP PROTEIN SEQUENCE OF 24-1474, SUBUNIT, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND DISULFIDE BONDS.
RX PubMed=6203908;
RA Sottrup-Jensen L., Stepanik T.M., Kristensen T., Wierzbicki D.M.,
RA Jones C.M., Loenblad P.B., Magnusson S., Petersen T.E.;
RT "Primary structure of human alpha 2-macroglobulin. V. The complete
RT structure.";
RL J. Biol. Chem. 259:8318-8327(1984).
RN [9]
RP ERRATUM.
RA Sottrup-Jensen L., Stepanik T.M., Kristensen T., Wierzbicki D.M.,
RA Jones C.M., Loenblad P.B., Magnusson S., Petersen T.E.;
RL J. Biol. Chem. 260:6500-6500(1985).
RN [10]
RP PROTEIN SEQUENCE OF 273-286 AND 426-436, AND DISULFIDE BONDS.
RX PubMed=2430963;
RA Jensen P.E.H., Sottrup-Jensen L.;
RT "Primary structure of human alpha 2-macroglobulin. Complete disulfide
RT bridge assignment and localization of two interchain bridges in the
RT dimeric proteinase binding unit.";
RL J. Biol. Chem. 261:15863-15869(1986).
RN [11]
RP PROTEIN SEQUENCE OF 672-747.
RX PubMed=1692292; DOI=10.1016/0014-5793(90)80226-9;
RA Marynen P., Devriendt K., van den Berghe H., Cassiman J.-J.;
RT "A genetic polymorphism in a functional domain of human pregnancy zone
RT protein: the bait region. Genomic structure of the bait domains of
RT human pregnancy zone protein and alpha 2 macroglobulin.";
RL FEBS Lett. 262:349-352(1990).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 672-746, AND VARIANT TYR-972.
RX PubMed=1370808; DOI=10.1007/BF00197266;
RA Poller W., Faber J.-P., Klobeck G., Olek K.;
RT "Cloning of the human alpha 2-macroglobulin gene and detection of
RT mutations in two functional domains: the bait region and the
RT thiolester site.";
RL Hum. Genet. 88:313-319(1992).
RN [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 832-1474.
RC TISSUE=Liver;
RX PubMed=2408344; DOI=10.1007/BF01534685;
RA Bell G.I., Rall L.B., Sanchez-Pescador R., Merryweather J.P.,
RA Scott J., Eddy R.L., Shows T.B.;
RT "Human alpha 2-macroglobulin gene is located on chromosome 12.";
RL Somat. Cell Mol. Genet. 11:285-289(1985).
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1208-1474.
RC TISSUE=Aorta;
RA Liu B., Zhao B., Wang X.Y., Xu Y.Y., Liu Y.Q., Song L., Ye J.,
RA Sheng H., Gao Y., Zhang C.L., Wei Y.J., Zhang J., Song L., Jiang Y.X.,
RA Zhao Z.W., Ding J.F., Liu L.S., Gao R.L., Wu Q.Y., Qiang B.Q.,
RA Yuan J.G., Liew C.C., Zhao M.S., Hui R.T.;
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [15]
RP INHIBITORY SITE.
RX PubMed=6167263; DOI=10.1016/S0006-291X(81)80055-1;
RA Hall P.K., Nelles L.P., Travis J., Roberts R.C.;
RT "Proteolytic cleavage sites on alpha 2-macroglobulin resulting in
RT proteinase binding are different for trypsin and Staphylococcus aureus
RT V-8 proteinase.";
RL Biochem. Biophys. Res. Commun. 100:8-16(1981).
RN [16]
RP INHIBITORY SITE.
RX PubMed=6165619; DOI=10.1016/0014-5793(81)80197-4;
RA Sottrup-Jensen L., Loenblad P.B., Stepanik T.M., Petersen T.E.,
RA Magnusson S., Joernvall H.;
RT "Primary structure of the 'bait' region for proteinases in alpha 2-
RT macroglobulin. Nature of the complex.";
RL FEBS Lett. 127:167-173(1981).
RN [17]
RP INHIBITORY SITE.
RX PubMed=6172288; DOI=10.1016/0014-5793(81)80804-6;
RA Mortensen S.B., Sottrup-Jensen L., Hansen H.F., Petersen T.E.,
RA Magnusson S.;
RT "Primary and secondary cleavage sites in the bait region of alpha 2-
RT macroglobulin.";
RL FEBS Lett. 135:295-300(1981).
RN [18]
RP INHIBITORY SITE.
RX PubMed=6195065;
RA Virca G.D., Salvesen G.S., Travis J.;
RT "Human neutrophil elastase and cathepsin G cleavage sites in the bait
RT region of alpha 2-macroglobulin. Proposed structural limits of the
RT bait region.";
RL Hoppe-Seyler's Z. Physiol. Chem. 364:1297-1302(1983).
RN [19]
RP GLYCOSYLATION AT ASN-991.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [20]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-869 AND ASN-1424, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-55; ASN-247; ASN-396;
RP ASN-410; ASN-869; ASN-991 AND ASN-1424, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-396; ASN-991 AND ASN-1424,
RP AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [23]
RP GLYCOSYLATION AT ASN-55 AND ASN-1424.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP STRUCTURE BY NMR OF 1337-1474.
RX PubMed=9865955;
RA Huang W., Dolmer K., Liao X., Gettins P.G.W.;
RT "Localization of basic residues required for receptor binding to the
RT single alpha-helix of the receptor binding domain of human alpha2-
RT macroglobulin.";
RL Protein Sci. 7:2602-2612(1998).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 126-227, AND DOMAIN
RP STRUCTURE.
RX PubMed=17608619; DOI=10.1042/BJ20070764;
RA Doan N., Gettins P.G.W.;
RT "Human alpha2-macroglobulin is composed of multiple domains, as
RT predicted by homology with complement component C3.";
RL Biochem. J. 407:23-30(2007).
RN [27]
RP VARIANT VAL-1000.
RX PubMed=1707161; DOI=10.1093/nar/19.1.198-a;
RA Poller W., Faber J.-P., Olek K.;
RT "Sequence polymorphism in the human alpha2-macroglobulin (A2M) gene.";
RL Nucleic Acids Res. 19:198-198(1991).
CC -!- FUNCTION: Is able to inhibit all four classes of proteinases by a
CC unique 'trapping' mechanism. This protein has a peptide stretch,
CC called the 'bait region' which contains specific cleavage sites
CC for different proteinases. When a proteinase cleaves the bait
CC region, a conformational change is induced in the protein which
CC traps the proteinase. The entrapped enzyme remains active against
CC low molecular weight substrates (activity against high molecular
CC weight substrates is greatly reduced). Following cleavage in the
CC bait region a thioester bond is hydrolyzed and mediates the
CC covalent binding of the protein to the proteinase.
CC -!- SUBUNIT: Homotetramer; disulfide-linked.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Secreted in plasma.
CC -!- DEVELOPMENTAL STAGE: Contrary to the rat protein, which is an
CC acute phase protein, this protein is always present at high levels
CC in circulation.
CC -!- SIMILARITY: Belongs to the protease inhibitor I39 (alpha-2-
CC macroglobulin) family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAT02228.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC Sequence=BAD92851.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Alpha-2 macroglobulin entry;
CC URL="http://en.wikipedia.org/wiki/Alpha_2-macroglobulin";
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DR EMBL; M11313; AAA51551.1; -; mRNA.
DR EMBL; AY591530; AAT02228.1; ALT_INIT; mRNA.
DR EMBL; AB209614; BAD92851.1; ALT_INIT; mRNA.
DR EMBL; CR749334; CAH18188.1; -; mRNA.
DR EMBL; AC007436; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC026246; AAH26246.1; -; mRNA.
DR EMBL; BC040071; AAH40071.1; -; mRNA.
DR EMBL; Z11711; CAA77774.1; -; Genomic_DNA.
DR EMBL; X68728; CAA48670.1; -; Genomic_DNA.
DR EMBL; X68729; CAA48670.1; JOINED; Genomic_DNA.
DR EMBL; M36501; AAA51552.1; -; mRNA.
DR EMBL; AF109189; AAQ13498.1; -; mRNA.
DR PIR; A94033; MAHU.
DR RefSeq; NP_000005.2; NM_000014.4.
DR UniGene; Hs.212838; -.
DR PDB; 1BV8; NMR; -; A=1337-1474.
DR PDB; 2P9R; X-ray; 2.30 A; A/B=126-227.
DR PDB; 4ACQ; X-ray; 4.30 A; A/B/C/D=24-1474.
DR PDBsum; 1BV8; -.
DR PDBsum; 2P9R; -.
DR PDBsum; 4ACQ; -.
DR ProteinModelPortal; P01023; -.
DR SMR; P01023; 126-227, 1338-1474.
DR DIP; DIP-1118N; -.
DR IntAct; P01023; 93.
DR MINT; MINT-122288; -.
DR STRING; 9606.ENSP00000323929; -.
DR DrugBank; DB00626; Bacitracin.
DR DrugBank; DB00102; Becaplermin.
DR MEROPS; I39.001; -.
DR PhosphoSite; P01023; -.
DR DMDM; 308153640; -.
DR DOSAC-COBS-2DPAGE; P01023; -.
DR SWISS-2DPAGE; P01023; -.
DR PaxDb; P01023; -.
DR PeptideAtlas; P01023; -.
DR PRIDE; P01023; -.
DR Ensembl; ENST00000318602; ENSP00000323929; ENSG00000175899.
DR GeneID; 2; -.
DR KEGG; hsa:2; -.
DR UCSC; uc001qvk.1; human.
DR CTD; 2; -.
DR GeneCards; GC12M009220; -.
DR H-InvDB; HIX0026392; -.
DR HGNC; HGNC:7; A2M.
DR HPA; CAB017621; -.
DR HPA; HPA002265; -.
DR MIM; 103950; gene.
DR neXtProt; NX_P01023; -.
DR PharmGKB; PA24357; -.
DR eggNOG; COG2373; -.
DR HOVERGEN; HBG000039; -.
DR KO; K03910; -.
DR OMA; QTVQAHY; -.
DR OrthoDB; EOG7DJSKB; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; A2M; human.
DR EvolutionaryTrace; P01023; -.
DR GenomeRNAi; 2; -.
DR NextBio; 5; -.
DR PRO; PR:P01023; -.
DR ArrayExpress; P01023; -.
DR Bgee; P01023; -.
DR CleanEx; HS_A2M; -.
DR Genevestigator; P01023; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IEA:InterPro.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0019966; F:interleukin-1 binding; IDA:UniProtKB.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:UniProtKB.
DR GO; GO:0043120; F:tumor necrosis factor binding; IDA:UniProtKB.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; TAS:Reactome.
DR GO; GO:0001869; P:negative regulation of complement activation, lectin pathway; IDA:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0048863; P:stem cell differentiation; IEA:Ensembl.
DR Gene3D; 2.60.40.690; -; 1.
DR InterPro; IPR009048; A-macroglobulin_rcpt-bd.
DR InterPro; IPR011626; A2M_comp.
DR InterPro; IPR002890; A2M_N.
DR InterPro; IPR011625; A2M_N_2.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR001599; Macroglobln_a2.
DR InterPro; IPR019742; MacrogloblnA2_CS.
DR InterPro; IPR019565; MacrogloblnA2_thiol-ester-bond.
DR InterPro; IPR008930; Terpenoid_cyclase/PrenylTrfase.
DR InterPro; IPR010916; TonB_box_CS.
DR Pfam; PF00207; A2M; 1.
DR Pfam; PF07678; A2M_comp; 1.
DR Pfam; PF01835; A2M_N; 1.
DR Pfam; PF07703; A2M_N_2; 1.
DR Pfam; PF07677; A2M_recep; 1.
DR Pfam; PF10569; Thiol-ester_cl; 1.
DR SUPFAM; SSF48239; SSF48239; 1.
DR SUPFAM; SSF49410; SSF49410; 1.
DR SUPFAM; SSF81296; SSF81296; 1.
DR PROSITE; PS00477; ALPHA_2_MACROGLOBULIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Bait region; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Isopeptide bond; Polymorphism; Protease inhibitor; Reference proteome;
KW Secreted; Serine protease inhibitor; Signal; Thioester bond.
FT SIGNAL 1 23
FT CHAIN 24 1474 Alpha-2-macroglobulin.
FT /FTId=PRO_0000000055.
FT REGION 690 728 Bait region.
FT REGION 704 709 Inhibitory.
FT REGION 719 723 Inhibitory.
FT REGION 730 735 Inhibitory.
FT CARBOHYD 55 55 N-linked (GlcNAc...) (complex).
FT CARBOHYD 70 70 N-linked (GlcNAc...).
FT CARBOHYD 247 247 N-linked (GlcNAc...).
FT CARBOHYD 396 396 N-linked (GlcNAc...).
FT CARBOHYD 410 410 N-linked (GlcNAc...).
FT CARBOHYD 869 869 N-linked (GlcNAc...).
FT CARBOHYD 991 991 N-linked (GlcNAc...).
FT CARBOHYD 1424 1424 N-linked (GlcNAc...) (complex).
FT DISULFID 48 86
FT DISULFID 251 299
FT DISULFID 269 287
FT DISULFID 278 278 Interchain (with C-431).
FT DISULFID 431 431 Interchain (with C-278).
FT DISULFID 470 563
FT DISULFID 595 771
FT DISULFID 642 689
FT DISULFID 821 849
FT DISULFID 847 883
FT DISULFID 921 1321
FT DISULFID 1079 1127
FT DISULFID 1352 1467
FT CROSSLNK 693 693 Isoglutamyl lysine isopeptide (Gln-Lys)
FT (interchain with K-? in other proteins)
FT (Potential).
FT CROSSLNK 694 694 Isoglutamyl lysine isopeptide (Gln-Lys)
FT (interchain with K-? in other proteins)
FT (Potential).
FT CROSSLNK 972 975 Isoglutamyl cysteine thioester (Cys-Gln).
FT VARIANT 639 639 N -> D (in dbSNP:rs226405).
FT /FTId=VAR_026820.
FT VARIANT 704 704 R -> H (in dbSNP:rs1800434).
FT /FTId=VAR_000012.
FT VARIANT 815 815 L -> Q (in dbSNP:rs3180392).
FT /FTId=VAR_026821.
FT VARIANT 972 972 C -> Y (probably interferes with the
FT activity; dbSNP:rs1800433).
FT /FTId=VAR_000013.
FT VARIANT 1000 1000 I -> V (in dbSNP:rs669).
FT /FTId=VAR_000014.
FT CONFLICT 63 63 Missing (in Ref. 8; AA sequence).
FT CONFLICT 82 82 D -> V (in Ref. 3; AAT02228).
FT CONFLICT 350 353 LSFV -> ACCS (in Ref. 6; AAH26246).
FT CONFLICT 563 563 C -> E (in Ref. 8; AA sequence).
FT CONFLICT 844 844 A -> V (in Ref. 4; BAD92851).
FT CONFLICT 872 872 V -> M (in Ref. 5; CAH18188).
FT CONFLICT 1148 1148 A -> D (in Ref. 13; AAA51552).
FT CONFLICT 1195 1195 H -> D (in Ref. 13; AAA51552).
FT STRAND 128 134
FT STRAND 136 138
FT STRAND 143 151
FT HELIX 153 155
FT STRAND 161 168
FT STRAND 174 182
FT STRAND 187 193
FT STRAND 201 208
FT STRAND 214 221
FT STRAND 1341 1347
FT HELIX 1355 1359
FT STRAND 1360 1369
FT STRAND 1379 1384
FT STRAND 1389 1391
FT HELIX 1393 1400
FT TURN 1401 1403
FT STRAND 1407 1410
FT STRAND 1412 1419
FT STRAND 1427 1434
FT STRAND 1445 1450
FT STRAND 1454 1456
FT STRAND 1459 1463
SQ SEQUENCE 1474 AA; 163291 MW; 0A46DF09EFD3CF40 CRC64;
MGKNKLLHPS LVLLLLVLLP TDASVSGKPQ YMVLVPSLLH TETTEKGCVL LSYLNETVTV
SASLESVRGN RSLFTDLEAE NDVLHCVAFA VPKSSSNEEV MFLTVQVKGP TQEFKKRTTV
MVKNEDSLVF VQTDKSIYKP GQTVKFRVVS MDENFHPLNE LIPLVYIQDP KGNRIAQWQS
FQLEGGLKQF SFPLSSEPFQ GSYKVVVQKK SGGRTEHPFT VEEFVLPKFE VQVTVPKIIT
ILEEEMNVSV CGLYTYGKPV PGHVTVSICR KYSDASDCHG EDSQAFCEKF SGQLNSHGCF
YQQVKTKVFQ LKRKEYEMKL HTEAQIQEEG TVVELTGRQS SEITRTITKL SFVKVDSHFR
QGIPFFGQVR LVDGKGVPIP NKVIFIRGNE ANYYSNATTD EHGLVQFSIN TTNVMGTSLT
VRVNYKDRSP CYGYQWVSEE HEEAHHTAYL VFSPSKSFVH LEPMSHELPC GHTQTVQAHY
ILNGGTLLGL KKLSFYYLIM AKGGIVRTGT HGLLVKQEDM KGHFSISIPV KSDIAPVARL
LIYAVLPTGD VIGDSAKYDV ENCLANKVDL SFSPSQSLPA SHAHLRVTAA PQSVCALRAV
DQSVLLMKPD AELSASSVYN LLPEKDLTGF PGPLNDQDNE DCINRHNVYI NGITYTPVSS
TNEKDMYSFL EDMGLKAFTN SKIRKPKMCP QLQQYEMHGP EGLRVGFYES DVMGRGHARL
VHVEEPHTET VRKYFPETWI WDLVVVNSAG VAEVGVTVPD TITEWKAGAF CLSEDAGLGI
SSTASLRAFQ PFFVELTMPY SVIRGEAFTL KATVLNYLPK CIRVSVQLEA SPAFLAVPVE
KEQAPHCICA NGRQTVSWAV TPKSLGNVNF TVSAEALESQ ELCGTEVPSV PEHGRKDTVI
KPLLVEPEGL EKETTFNSLL CPSGGEVSEE LSLKLPPNVV EESARASVSV LGDILGSAMQ
NTQNLLQMPY GCGEQNMVLF APNIYVLDYL NETQQLTPEI KSKAIGYLNT GYQRQLNYKH
YDGSYSTFGE RYGRNQGNTW LTAFVLKTFA QARAYIFIDE AHITQALIWL SQRQKDNGCF
RSSGSLLNNA IKGGVEDEVT LSAYITIALL EIPLTVTHPV VRNALFCLES AWKTAQEGDH
GSHVYTKALL AYAFALAGNQ DKRKEVLKSL NEEAVKKDNS VHWERPQKPK APVGHFYEPQ
APSAEVEMTS YVLLAYLTAQ PAPTSEDLTS ATNIVKWITK QQNAQGGFSS TQDTVVALHA
LSKYGAATFT RTGKAAQVTI QSSGTFSSKF QVDNNNRLLL QQVSLPELPG EYSMKVTGEG
CVYLQTSLKY NILPEKEEFP FALGVQTLPQ TCDEPKAHTS FQISLSVSYT GSRSASNMAI
VDVKMVSGFI PLKPTVKMLE RSNHVSRTEV SSNHVLIYLD KVSNQTLSLF FTVLQDVPVR
DLKPAIVKVY DYYETDEFAI AEYNAPCSKD LGNA
//
ID A2MG_HUMAN Reviewed; 1474 AA.
AC P01023; Q13677; Q59F47; Q5QTS0; Q68DN2; Q6PIY3; Q6PN97;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-OCT-2010, sequence version 3.
DT 22-JAN-2014, entry version 166.
DE RecName: Full=Alpha-2-macroglobulin;
DE Short=Alpha-2-M;
DE AltName: Full=C3 and PZP-like alpha-2-macroglobulin domain-containing protein 5;
DE Flags: Precursor;
GN Name=A2M; Synonyms=CPAMD5; ORFNames=FWP007;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS ASP-639 AND VAL-1000.
RX PubMed=2581245; DOI=10.1073/pnas.82.8.2282;
RA Kan C.-C., Solomon E., Belt K.T., Chain A.C., Hiorns L.R., Fey G.H.;
RT "Nucleotide sequence of cDNA encoding human alpha 2-macroglobulin and
RT assignment of the chromosomal locus.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:2282-2286(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS ASP-639 AND VAL-1000.
RC TISSUE=Prostate;
RX PubMed=15611997; DOI=10.1002/pros.20183;
RA Lin V.K., Wang S.-Y., Boetticher N.C., Vazquez D.V., Saboorian H.,
RA McConnell J.D., Roehrborn C.G.;
RT "Alpha(2) macroglobulin, a PSA-binding protein, is expressed in human
RT prostate stroma.";
RL Prostate 63:299-308(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ASP-639.
RC TISSUE=Spleen;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ASP-639 AND
RP VAL-1000.
RC TISSUE=Liver;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ASP-639 AND
RP VAL-1000.
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-29.
RC TISSUE=Placenta;
RX PubMed=1374237; DOI=10.1016/0006-291X(92)90631-T;
RA Matthijs G., Devriendt K., Cassiman J.-J., van den Berghe H.,
RA Marynen P.;
RT "Structure of the human alpha-2 macroglobulin gene and its promotor.";
RL Biochem. Biophys. Res. Commun. 184:596-603(1992).
RN [8]
RP PROTEIN SEQUENCE OF 24-1474, SUBUNIT, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND DISULFIDE BONDS.
RX PubMed=6203908;
RA Sottrup-Jensen L., Stepanik T.M., Kristensen T., Wierzbicki D.M.,
RA Jones C.M., Loenblad P.B., Magnusson S., Petersen T.E.;
RT "Primary structure of human alpha 2-macroglobulin. V. The complete
RT structure.";
RL J. Biol. Chem. 259:8318-8327(1984).
RN [9]
RP ERRATUM.
RA Sottrup-Jensen L., Stepanik T.M., Kristensen T., Wierzbicki D.M.,
RA Jones C.M., Loenblad P.B., Magnusson S., Petersen T.E.;
RL J. Biol. Chem. 260:6500-6500(1985).
RN [10]
RP PROTEIN SEQUENCE OF 273-286 AND 426-436, AND DISULFIDE BONDS.
RX PubMed=2430963;
RA Jensen P.E.H., Sottrup-Jensen L.;
RT "Primary structure of human alpha 2-macroglobulin. Complete disulfide
RT bridge assignment and localization of two interchain bridges in the
RT dimeric proteinase binding unit.";
RL J. Biol. Chem. 261:15863-15869(1986).
RN [11]
RP PROTEIN SEQUENCE OF 672-747.
RX PubMed=1692292; DOI=10.1016/0014-5793(90)80226-9;
RA Marynen P., Devriendt K., van den Berghe H., Cassiman J.-J.;
RT "A genetic polymorphism in a functional domain of human pregnancy zone
RT protein: the bait region. Genomic structure of the bait domains of
RT human pregnancy zone protein and alpha 2 macroglobulin.";
RL FEBS Lett. 262:349-352(1990).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 672-746, AND VARIANT TYR-972.
RX PubMed=1370808; DOI=10.1007/BF00197266;
RA Poller W., Faber J.-P., Klobeck G., Olek K.;
RT "Cloning of the human alpha 2-macroglobulin gene and detection of
RT mutations in two functional domains: the bait region and the
RT thiolester site.";
RL Hum. Genet. 88:313-319(1992).
RN [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 832-1474.
RC TISSUE=Liver;
RX PubMed=2408344; DOI=10.1007/BF01534685;
RA Bell G.I., Rall L.B., Sanchez-Pescador R., Merryweather J.P.,
RA Scott J., Eddy R.L., Shows T.B.;
RT "Human alpha 2-macroglobulin gene is located on chromosome 12.";
RL Somat. Cell Mol. Genet. 11:285-289(1985).
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1208-1474.
RC TISSUE=Aorta;
RA Liu B., Zhao B., Wang X.Y., Xu Y.Y., Liu Y.Q., Song L., Ye J.,
RA Sheng H., Gao Y., Zhang C.L., Wei Y.J., Zhang J., Song L., Jiang Y.X.,
RA Zhao Z.W., Ding J.F., Liu L.S., Gao R.L., Wu Q.Y., Qiang B.Q.,
RA Yuan J.G., Liew C.C., Zhao M.S., Hui R.T.;
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [15]
RP INHIBITORY SITE.
RX PubMed=6167263; DOI=10.1016/S0006-291X(81)80055-1;
RA Hall P.K., Nelles L.P., Travis J., Roberts R.C.;
RT "Proteolytic cleavage sites on alpha 2-macroglobulin resulting in
RT proteinase binding are different for trypsin and Staphylococcus aureus
RT V-8 proteinase.";
RL Biochem. Biophys. Res. Commun. 100:8-16(1981).
RN [16]
RP INHIBITORY SITE.
RX PubMed=6165619; DOI=10.1016/0014-5793(81)80197-4;
RA Sottrup-Jensen L., Loenblad P.B., Stepanik T.M., Petersen T.E.,
RA Magnusson S., Joernvall H.;
RT "Primary structure of the 'bait' region for proteinases in alpha 2-
RT macroglobulin. Nature of the complex.";
RL FEBS Lett. 127:167-173(1981).
RN [17]
RP INHIBITORY SITE.
RX PubMed=6172288; DOI=10.1016/0014-5793(81)80804-6;
RA Mortensen S.B., Sottrup-Jensen L., Hansen H.F., Petersen T.E.,
RA Magnusson S.;
RT "Primary and secondary cleavage sites in the bait region of alpha 2-
RT macroglobulin.";
RL FEBS Lett. 135:295-300(1981).
RN [18]
RP INHIBITORY SITE.
RX PubMed=6195065;
RA Virca G.D., Salvesen G.S., Travis J.;
RT "Human neutrophil elastase and cathepsin G cleavage sites in the bait
RT region of alpha 2-macroglobulin. Proposed structural limits of the
RT bait region.";
RL Hoppe-Seyler's Z. Physiol. Chem. 364:1297-1302(1983).
RN [19]
RP GLYCOSYLATION AT ASN-991.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [20]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-869 AND ASN-1424, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-55; ASN-247; ASN-396;
RP ASN-410; ASN-869; ASN-991 AND ASN-1424, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-396; ASN-991 AND ASN-1424,
RP AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [23]
RP GLYCOSYLATION AT ASN-55 AND ASN-1424.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP STRUCTURE BY NMR OF 1337-1474.
RX PubMed=9865955;
RA Huang W., Dolmer K., Liao X., Gettins P.G.W.;
RT "Localization of basic residues required for receptor binding to the
RT single alpha-helix of the receptor binding domain of human alpha2-
RT macroglobulin.";
RL Protein Sci. 7:2602-2612(1998).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 126-227, AND DOMAIN
RP STRUCTURE.
RX PubMed=17608619; DOI=10.1042/BJ20070764;
RA Doan N., Gettins P.G.W.;
RT "Human alpha2-macroglobulin is composed of multiple domains, as
RT predicted by homology with complement component C3.";
RL Biochem. J. 407:23-30(2007).
RN [27]
RP VARIANT VAL-1000.
RX PubMed=1707161; DOI=10.1093/nar/19.1.198-a;
RA Poller W., Faber J.-P., Olek K.;
RT "Sequence polymorphism in the human alpha2-macroglobulin (A2M) gene.";
RL Nucleic Acids Res. 19:198-198(1991).
CC -!- FUNCTION: Is able to inhibit all four classes of proteinases by a
CC unique 'trapping' mechanism. This protein has a peptide stretch,
CC called the 'bait region' which contains specific cleavage sites
CC for different proteinases. When a proteinase cleaves the bait
CC region, a conformational change is induced in the protein which
CC traps the proteinase. The entrapped enzyme remains active against
CC low molecular weight substrates (activity against high molecular
CC weight substrates is greatly reduced). Following cleavage in the
CC bait region a thioester bond is hydrolyzed and mediates the
CC covalent binding of the protein to the proteinase.
CC -!- SUBUNIT: Homotetramer; disulfide-linked.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Secreted in plasma.
CC -!- DEVELOPMENTAL STAGE: Contrary to the rat protein, which is an
CC acute phase protein, this protein is always present at high levels
CC in circulation.
CC -!- SIMILARITY: Belongs to the protease inhibitor I39 (alpha-2-
CC macroglobulin) family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAT02228.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC Sequence=BAD92851.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Alpha-2 macroglobulin entry;
CC URL="http://en.wikipedia.org/wiki/Alpha_2-macroglobulin";
CC -----------------------------------------------------------------------
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DR EMBL; M11313; AAA51551.1; -; mRNA.
DR EMBL; AY591530; AAT02228.1; ALT_INIT; mRNA.
DR EMBL; AB209614; BAD92851.1; ALT_INIT; mRNA.
DR EMBL; CR749334; CAH18188.1; -; mRNA.
DR EMBL; AC007436; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC026246; AAH26246.1; -; mRNA.
DR EMBL; BC040071; AAH40071.1; -; mRNA.
DR EMBL; Z11711; CAA77774.1; -; Genomic_DNA.
DR EMBL; X68728; CAA48670.1; -; Genomic_DNA.
DR EMBL; X68729; CAA48670.1; JOINED; Genomic_DNA.
DR EMBL; M36501; AAA51552.1; -; mRNA.
DR EMBL; AF109189; AAQ13498.1; -; mRNA.
DR PIR; A94033; MAHU.
DR RefSeq; NP_000005.2; NM_000014.4.
DR UniGene; Hs.212838; -.
DR PDB; 1BV8; NMR; -; A=1337-1474.
DR PDB; 2P9R; X-ray; 2.30 A; A/B=126-227.
DR PDB; 4ACQ; X-ray; 4.30 A; A/B/C/D=24-1474.
DR PDBsum; 1BV8; -.
DR PDBsum; 2P9R; -.
DR PDBsum; 4ACQ; -.
DR ProteinModelPortal; P01023; -.
DR SMR; P01023; 126-227, 1338-1474.
DR DIP; DIP-1118N; -.
DR IntAct; P01023; 93.
DR MINT; MINT-122288; -.
DR STRING; 9606.ENSP00000323929; -.
DR DrugBank; DB00626; Bacitracin.
DR DrugBank; DB00102; Becaplermin.
DR MEROPS; I39.001; -.
DR PhosphoSite; P01023; -.
DR DMDM; 308153640; -.
DR DOSAC-COBS-2DPAGE; P01023; -.
DR SWISS-2DPAGE; P01023; -.
DR PaxDb; P01023; -.
DR PeptideAtlas; P01023; -.
DR PRIDE; P01023; -.
DR Ensembl; ENST00000318602; ENSP00000323929; ENSG00000175899.
DR GeneID; 2; -.
DR KEGG; hsa:2; -.
DR UCSC; uc001qvk.1; human.
DR CTD; 2; -.
DR GeneCards; GC12M009220; -.
DR H-InvDB; HIX0026392; -.
DR HGNC; HGNC:7; A2M.
DR HPA; CAB017621; -.
DR HPA; HPA002265; -.
DR MIM; 103950; gene.
DR neXtProt; NX_P01023; -.
DR PharmGKB; PA24357; -.
DR eggNOG; COG2373; -.
DR HOVERGEN; HBG000039; -.
DR KO; K03910; -.
DR OMA; QTVQAHY; -.
DR OrthoDB; EOG7DJSKB; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; A2M; human.
DR EvolutionaryTrace; P01023; -.
DR GenomeRNAi; 2; -.
DR NextBio; 5; -.
DR PRO; PR:P01023; -.
DR ArrayExpress; P01023; -.
DR Bgee; P01023; -.
DR CleanEx; HS_A2M; -.
DR Genevestigator; P01023; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IEA:InterPro.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0019966; F:interleukin-1 binding; IDA:UniProtKB.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:UniProtKB.
DR GO; GO:0043120; F:tumor necrosis factor binding; IDA:UniProtKB.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; TAS:Reactome.
DR GO; GO:0001869; P:negative regulation of complement activation, lectin pathway; IDA:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0048863; P:stem cell differentiation; IEA:Ensembl.
DR Gene3D; 2.60.40.690; -; 1.
DR InterPro; IPR009048; A-macroglobulin_rcpt-bd.
DR InterPro; IPR011626; A2M_comp.
DR InterPro; IPR002890; A2M_N.
DR InterPro; IPR011625; A2M_N_2.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR001599; Macroglobln_a2.
DR InterPro; IPR019742; MacrogloblnA2_CS.
DR InterPro; IPR019565; MacrogloblnA2_thiol-ester-bond.
DR InterPro; IPR008930; Terpenoid_cyclase/PrenylTrfase.
DR InterPro; IPR010916; TonB_box_CS.
DR Pfam; PF00207; A2M; 1.
DR Pfam; PF07678; A2M_comp; 1.
DR Pfam; PF01835; A2M_N; 1.
DR Pfam; PF07703; A2M_N_2; 1.
DR Pfam; PF07677; A2M_recep; 1.
DR Pfam; PF10569; Thiol-ester_cl; 1.
DR SUPFAM; SSF48239; SSF48239; 1.
DR SUPFAM; SSF49410; SSF49410; 1.
DR SUPFAM; SSF81296; SSF81296; 1.
DR PROSITE; PS00477; ALPHA_2_MACROGLOBULIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Bait region; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Isopeptide bond; Polymorphism; Protease inhibitor; Reference proteome;
KW Secreted; Serine protease inhibitor; Signal; Thioester bond.
FT SIGNAL 1 23
FT CHAIN 24 1474 Alpha-2-macroglobulin.
FT /FTId=PRO_0000000055.
FT REGION 690 728 Bait region.
FT REGION 704 709 Inhibitory.
FT REGION 719 723 Inhibitory.
FT REGION 730 735 Inhibitory.
FT CARBOHYD 55 55 N-linked (GlcNAc...) (complex).
FT CARBOHYD 70 70 N-linked (GlcNAc...).
FT CARBOHYD 247 247 N-linked (GlcNAc...).
FT CARBOHYD 396 396 N-linked (GlcNAc...).
FT CARBOHYD 410 410 N-linked (GlcNAc...).
FT CARBOHYD 869 869 N-linked (GlcNAc...).
FT CARBOHYD 991 991 N-linked (GlcNAc...).
FT CARBOHYD 1424 1424 N-linked (GlcNAc...) (complex).
FT DISULFID 48 86
FT DISULFID 251 299
FT DISULFID 269 287
FT DISULFID 278 278 Interchain (with C-431).
FT DISULFID 431 431 Interchain (with C-278).
FT DISULFID 470 563
FT DISULFID 595 771
FT DISULFID 642 689
FT DISULFID 821 849
FT DISULFID 847 883
FT DISULFID 921 1321
FT DISULFID 1079 1127
FT DISULFID 1352 1467
FT CROSSLNK 693 693 Isoglutamyl lysine isopeptide (Gln-Lys)
FT (interchain with K-? in other proteins)
FT (Potential).
FT CROSSLNK 694 694 Isoglutamyl lysine isopeptide (Gln-Lys)
FT (interchain with K-? in other proteins)
FT (Potential).
FT CROSSLNK 972 975 Isoglutamyl cysteine thioester (Cys-Gln).
FT VARIANT 639 639 N -> D (in dbSNP:rs226405).
FT /FTId=VAR_026820.
FT VARIANT 704 704 R -> H (in dbSNP:rs1800434).
FT /FTId=VAR_000012.
FT VARIANT 815 815 L -> Q (in dbSNP:rs3180392).
FT /FTId=VAR_026821.
FT VARIANT 972 972 C -> Y (probably interferes with the
FT activity; dbSNP:rs1800433).
FT /FTId=VAR_000013.
FT VARIANT 1000 1000 I -> V (in dbSNP:rs669).
FT /FTId=VAR_000014.
FT CONFLICT 63 63 Missing (in Ref. 8; AA sequence).
FT CONFLICT 82 82 D -> V (in Ref. 3; AAT02228).
FT CONFLICT 350 353 LSFV -> ACCS (in Ref. 6; AAH26246).
FT CONFLICT 563 563 C -> E (in Ref. 8; AA sequence).
FT CONFLICT 844 844 A -> V (in Ref. 4; BAD92851).
FT CONFLICT 872 872 V -> M (in Ref. 5; CAH18188).
FT CONFLICT 1148 1148 A -> D (in Ref. 13; AAA51552).
FT CONFLICT 1195 1195 H -> D (in Ref. 13; AAA51552).
FT STRAND 128 134
FT STRAND 136 138
FT STRAND 143 151
FT HELIX 153 155
FT STRAND 161 168
FT STRAND 174 182
FT STRAND 187 193
FT STRAND 201 208
FT STRAND 214 221
FT STRAND 1341 1347
FT HELIX 1355 1359
FT STRAND 1360 1369
FT STRAND 1379 1384
FT STRAND 1389 1391
FT HELIX 1393 1400
FT TURN 1401 1403
FT STRAND 1407 1410
FT STRAND 1412 1419
FT STRAND 1427 1434
FT STRAND 1445 1450
FT STRAND 1454 1456
FT STRAND 1459 1463
SQ SEQUENCE 1474 AA; 163291 MW; 0A46DF09EFD3CF40 CRC64;
MGKNKLLHPS LVLLLLVLLP TDASVSGKPQ YMVLVPSLLH TETTEKGCVL LSYLNETVTV
SASLESVRGN RSLFTDLEAE NDVLHCVAFA VPKSSSNEEV MFLTVQVKGP TQEFKKRTTV
MVKNEDSLVF VQTDKSIYKP GQTVKFRVVS MDENFHPLNE LIPLVYIQDP KGNRIAQWQS
FQLEGGLKQF SFPLSSEPFQ GSYKVVVQKK SGGRTEHPFT VEEFVLPKFE VQVTVPKIIT
ILEEEMNVSV CGLYTYGKPV PGHVTVSICR KYSDASDCHG EDSQAFCEKF SGQLNSHGCF
YQQVKTKVFQ LKRKEYEMKL HTEAQIQEEG TVVELTGRQS SEITRTITKL SFVKVDSHFR
QGIPFFGQVR LVDGKGVPIP NKVIFIRGNE ANYYSNATTD EHGLVQFSIN TTNVMGTSLT
VRVNYKDRSP CYGYQWVSEE HEEAHHTAYL VFSPSKSFVH LEPMSHELPC GHTQTVQAHY
ILNGGTLLGL KKLSFYYLIM AKGGIVRTGT HGLLVKQEDM KGHFSISIPV KSDIAPVARL
LIYAVLPTGD VIGDSAKYDV ENCLANKVDL SFSPSQSLPA SHAHLRVTAA PQSVCALRAV
DQSVLLMKPD AELSASSVYN LLPEKDLTGF PGPLNDQDNE DCINRHNVYI NGITYTPVSS
TNEKDMYSFL EDMGLKAFTN SKIRKPKMCP QLQQYEMHGP EGLRVGFYES DVMGRGHARL
VHVEEPHTET VRKYFPETWI WDLVVVNSAG VAEVGVTVPD TITEWKAGAF CLSEDAGLGI
SSTASLRAFQ PFFVELTMPY SVIRGEAFTL KATVLNYLPK CIRVSVQLEA SPAFLAVPVE
KEQAPHCICA NGRQTVSWAV TPKSLGNVNF TVSAEALESQ ELCGTEVPSV PEHGRKDTVI
KPLLVEPEGL EKETTFNSLL CPSGGEVSEE LSLKLPPNVV EESARASVSV LGDILGSAMQ
NTQNLLQMPY GCGEQNMVLF APNIYVLDYL NETQQLTPEI KSKAIGYLNT GYQRQLNYKH
YDGSYSTFGE RYGRNQGNTW LTAFVLKTFA QARAYIFIDE AHITQALIWL SQRQKDNGCF
RSSGSLLNNA IKGGVEDEVT LSAYITIALL EIPLTVTHPV VRNALFCLES AWKTAQEGDH
GSHVYTKALL AYAFALAGNQ DKRKEVLKSL NEEAVKKDNS VHWERPQKPK APVGHFYEPQ
APSAEVEMTS YVLLAYLTAQ PAPTSEDLTS ATNIVKWITK QQNAQGGFSS TQDTVVALHA
LSKYGAATFT RTGKAAQVTI QSSGTFSSKF QVDNNNRLLL QQVSLPELPG EYSMKVTGEG
CVYLQTSLKY NILPEKEEFP FALGVQTLPQ TCDEPKAHTS FQISLSVSYT GSRSASNMAI
VDVKMVSGFI PLKPTVKMLE RSNHVSRTEV SSNHVLIYLD KVSNQTLSLF FTVLQDVPVR
DLKPAIVKVY DYYETDEFAI AEYNAPCSKD LGNA
//
MIM
103950
*RECORD*
*FIELD* NO
103950
*FIELD* TI
*103950 ALPHA-2-MACROGLOBULIN; A2M
;;MACROGLOBULIN, ALPHA-2
*FIELD* TX
DESCRIPTION
read more
A2M is a 718-kD homotetrameric glycoprotein of plasma and extracellular
spaces that was first recognized as a broad spectrum protease inhibitor.
A2M is activated by proteases with which it interacts, and this
proteolytic activation causes a conformational change that traps the
protease within the A2M homotetramer. In addition, A2M contains several
independent domains that function as carriers of specific growth factors
and/or binding sites for receptors. Activation of A2M by proteases
alters the interaction of A2M with these ligands and induces cell
signaling (summary by Mantuano et al., 2008).
CLONING
Using synthetic oligonucleotides as hybridization probes, Kan et al.
(1985) isolated A2M cDNA clones from a human liver cDNA library. The
coding sequence predicted a 1,451-amino acid polypeptide. Human A2M is a
tetramer of 4 identical 185-kD subunits arranged as a pair of dimers,
each consisting of 2 disulfide-linked monomers. The protein has a bait
region composed of peptide bonds for plasma proteases and a thiol ester
bond which, when hydrolyzed, leads to covalent bonding between the
protease and A2M.
GENE STRUCTURE
Matthijs et al. (1992) demonstrated that the A2M gene spans
approximately 48 kb and consists of 36 exons, from 21 to 229 bp in size
and with consensus splice sites. Intron sizes range from 125 bp to 7.5
kb. The A2M gene is present in single copy in the haploid genome. Umans
et al. (1994) found that the homologous gene in the mouse contains 36
exons, coding for a 4.8-kb cDNA. Including putative control elements in
the 5-prime flanking region, the gene covers about 45 kb. The promoter
region of the mouse A2m gene differed considerably from the known
promoter sequences of the human and rat genes.
MAPPING
Kan et al. (1985) assigned the A2M locus to chromosome 12 by Southern
blot analysis of DNA from a panel of mouse/human somatic cell hybrids,
using A2M cDNA as a hybridization probe. Fukushima et al. (1988)
assigned the A2M locus to 12p13.3-p12.3 by in situ hybridization.
Assignment of the A2M gene to human chromosome 12p13-p12.2 was confirmed
by Marynen et al. (1989) by use of in situ hybridization and somatic
cell hybrid DNA analysis. Devriendt et al. (1989) also assigned A2M to
12p13-p12 by analysis of somatic cell hybrids and in situ hybridization.
They showed, furthermore, that a closely related gene for pregnancy-zone
protein (PZP; 176420) and an A2M pseudogene map to the same region.
Hilliker et al. (1992) showed that the gene is located on mouse
chromosome 6 band F1-G3 in a syntenic group that has its human
counterpart on 12p13-p12.
GENE FUNCTION
Alpha-2-macroglobulin is, like alpha-1-antitrypsin, alpha-2-antiplasmin,
and antithrombin III, a protease inhibitor. It inhibits many proteases,
including trypsin, thrombin, and collagenase (Bergqvist and Nilsson,
1979).
Mantuano et al. (2008) used isolated recombinant human A2M protein
fragments, which they called FP3 and FP6, to characterize the cellular
functions of specific A2M domains. FP3 contains residues 591 to 774 of
A2M and includes the growth factor carrier sites, and FP6 contains
residues 1242 to 1451 of A2M and includes the LRP1 (107770) recognition
domain. FP6 rapidly and robustly activated Akt (see 164730) and Erk/MAP
kinases (see 176948) in cultured rat Schwann cells and PC12 rat
pheochromocytoma cells. FP6 also promoted neurite outgrowth and
expression of Gap43 (162060). These cell signaling events were mediated
by Lrp1 and depended on 2 lysines in FP6 that were required for Lrp1
binding. The ability of FP6 to trigger Lrp1-dependent cell signaling in
PC12 cells was reproduced by a purified 18-kD fragment of human plasma
A2M that included the LRP1 recognition domain. FP3 alone did not induce
cell signaling in rat Schwann and PC12 cells, but it blocked Ngf-beta
(NGFB; 162030)-induced activation of Akt and Erk/MAP kinases. FP3 did
not block activation of cell signaling induced by FP6.
Using mass spectrometry, Peslova et al. (2009) showed that hepcidin
(HAMP; 606464) in human plasma or serum was bound by albumin (ALB;
103600) and by A2M. Binding of hepcidin to albumin was nonspecific and
displayed nonsaturable kinetics. However, binding of hepcidin to A2M was
specific. Scatchard analysis estimated 2 hepcidin-binding sites per
inactive A2M molecule. Proteolytic activation of A2M resulted in a
sigmoidal binding curve, suggesting high-affinity cooperative allosteric
binding of 4 hepcidin molecules per active A2M molecule. The
hepcidin-A2M complex, but not the hepcidin-albumin complex, decreased
ferroportin (SLC40A1; 604653) expression in J774 murine macrophages more
effectively than hepcidin alone. Peslova et al. (2009) hypothesized that
A2M has a role in regulating hepcidin action by sequestration and
subsequent release.
MOLECULAR GENETICS
- Alpha-2-Macroglobulin Deficiency
By the electroimmunoassay of Laurell, Bergqvist and Nilsson (1979) found
alpha-2-macroglobulin deficiency (614036) in a 37-year-old man, his
mother, and one daughter. The deficient persons were apparently
heterozygotes. No clinical disadvantage resulted from the deficiency.
Poller et al. (1989) detected an alteration in the A2M gene in a patient
with serum A2M deficiency and chronic lung disease since childhood. The
alteration involved restriction sites detected with 10 different enzymes
and was thought to have been caused by major deletion or rearrangement
in the gene. Nine of the restriction enzymes used detected no
polymorphism in 40 healthy control subjects and 39 patients with chronic
obstructive pulmonary disease. The patient was heterozygous for the A2M
alteration; Poller et al. (1989) suggested that this was responsible for
the pulmonary disease.
- Association with Alzheimer Disease
Alpha-2-macroglobulin has been implicated in Alzheimer disease (AD;
104300) based on its ability to mediate the clearance and degradation of
A-beta, the major component of amyloid beta deposits. Blacker et al.
(1998) analyzed a deletion in the A2M gene (103950.0005) at the 5-prime
splice site of 'exon II' of the bait region (exon 18) and found that
inheritance of the deletion, designated A2M-2, conferred increased risk
for AD (Mantel-Haenzel odds ratio = 3.56, P = 0.001). The sibship
disequilibrium test (SDT) also revealed a significant association
between A2M and AD. These values were comparable to those obtained for
the APOE4 allele in the same sample, but in contrast to APOE4, A2M-2 did
not affect age of onset. The observed association that A2M with AD did
not appear to account for the previously published linkage of AD to
chromosome 12, which Blacker et al. (1998) were unable to confirm in
their sample. Thus, A2M, the A2M receptor (LRP1; 107770), and the genes
for 2 other LRP (low density lipoprotein-related protein) ligands, APOE
(107741) and APP (104760), had all been genetically linked to AD,
suggesting that these proteins may participate in the common
neuropathogenic pathway leading to the disease. Liao et al. (1998) found
an association between the val1000-to-ile polymorphism (103950.0001) and
AD.
In a study of AD in 3 samples of patients in the U.K., Dow et al. (1999)
failed to show a strong association between A2M-2 and AD risk.
Rudrasingham et al. (1999) did not find associations between AD and
A2M-2, or genotypes containing A2M-2, in a powerful, case-control
sample. Using the same family-based association methods employed by
Blacker et al. (1998), Rogaeva et al. (1999) also could not replicate
the association of A2M-2 in 2 comparable, independent familial AD
datasets or in a larger dataset of families from the same dataset tested
by Blacker et al. (1998). Furthermore, they were unable to document any
biologic effect of the A2M-2 allele on A2M RNA splicing, protein
monomeric molecular mass, or protein levels in brain, liver, or plasma
of A2M-2 carriers. Rogaeva et al. (1999) concluded that prior genetic
evidence for an AD susceptibility locus on chromosome 12 likely arose
from genetic variations other than in A2M-2 alleles. In a reply to these
criticisms, Blacker et al. (1999) commented that they did not find it
surprising that the case-control studies conducted by the groups of
Rudrasingham et al. (1999), Rogaeva et al. (1999), and Dow et al. (1999)
could not find an association. They suggested that the findings
highlighted differences between family-based and case-control
association studies. In an accompanying editorial (Anonymous, 1999), the
editor of Nature Genetics pointed out the difficulties in evaluating the
results of association studies. Unresolved fundamental issues included
such matters as the significance threshold of a true association
(especially in light of multiple-hypothesis testing aggravated by
publication bias for positive associations), how best to analyze a given
dataset, and what constitutes a valid refutation. The editors suggested
that they would expect manuscripts reporting genetic associations to
include an estimate of the effect size and to contain either a
replication in an independent sample or physiologically meaningful data
supporting a functional role of the polymorphism in question.
Saunders et al. (2003) resequenced the A2M locus and identified 7 novel
polymorphisms to test for genetic association with AD. Using the full
NIMH sample of 1,439 individuals in 437 families, they found significant
genetic association of the 5-bp deletion (103950.0005) and 2 novel
polymorphisms with AD. Substantial linkage disequilibrium was detected
across the gene as a whole, and haplotype analysis also showed
significant association between AD and groups of A2M polymorphisms.
Several of these polymorphisms and haplotypes remained significantly
associated with AD even after correction for multiple testing. The data
supported a potential role for A2M or a nearby gene in AD.
Bian et al. (2005) found no association of 6 A2M gene polymorphisms
(5-prime UTR A/G, dbSNP rs226379; T/G, dbSNP rs226380, intron 6 A/C;
exon 24 A/G; intron 27 A/G; intron 34 T/C, dbSNP rs3759277) with AD in a
study of 216 late-onset AD patients and 200 control subjects from the
Han Chinese population. Comparison of allele, genotype, and haplotype
frequencies for polymorphisms in A2M revealed no significant differences
between patients and control subjects.
Flachsbart et al. (2010) found that an A2M risk haplotype for Alzheimer
disease, comprising dbSNP rs3832852 and dbSNP rs669, was significantly
less frequent among 1,042 long-lived German individuals, aged 95 to 100
years, without AD compared to 1,040 younger German individuals, aged 60
to 75 years, without AD. The results suggested that the haplotype is a
mortality factor in the elderly. The findings were independent of APOE
status.
EVOLUTION
From comparison of the sequence of the subunit of human
alpha-2-macroglobulin with those of C3 (120700) and C4 (120810, 120820),
Sottrup-Jensen et al. (1985) concluded that these 3 proteins, which all
contain a unique activatable beta-cysteinyl-gamma-glutamyl thiol ester,
have a common evolutionary origin. C5 (120900) also shows sequence
homology to A2M.
ANIMAL MODEL
Umans et al. (1995) created mice lacking the alpha-2-macroglobulin gene.
The knockout mice were not only viable, but more resistant to endotoxin.
They produced normal-sized litters and showed no obvious phenotypic
abnormalities. Webb et al. (1996) demonstrated that murine
alpha-2-macroglobulin binds TGF-beta and inhibits TGF-beta-receptor
interactions. They suggested that these results explain the
endotoxin-insensitive phenotype of the knockout mice.
HISTORY
Leikola et al. (1972) identified an antigenic material of a high
molecular weight that they termed alpha-2-macroglobulin. They detected a
polymorphism in Japanese persons that was distinct from the Gm locus,
which determines the serologic type of gamma immunoglobulin (see
147100), the Am locus, which determines the serologic type of alpha
immunoglobulin (see 146900 and 147000), and haptoglobins (140100). It
was likewise distinct from Xm (314900), also a macroglobulin, as
indicated by the autosomal inheritance and specific tests. Gene
frequency of the allele whose product was demonstrated by the antiserum
was about 0.16 in Japanese. Using a rabbit antihuman serum, Gallango and
Castillo (1974) also described a polymorphism of alpha-2-macroglobulin.
This may be separate from that described by Leikola et al. (1972).
*FIELD* AV
.0001
ALPHA-2-MACROGLOBULIN POLYMORPHISM
ALZHEIMER DISEASE, SUSCEPTIBILITY TO, INCLUDED
A2M, VAL1000ILE
By direct genomic sequencing of the 2 exons encoding the bait region and
the exon encoding the thiolester site in 30 healthy individuals and in
30 patients with chronic lung disease, Poller et al. (1992) found a
sequence polymorphism near the thiolester site of the gene, changing
val1000 (GTC) to ile (ATC); the 2 alleles had frequencies of 0.30 and
0.70, respectively. No difference of A2M serum levels was observed for
these 2 alleles.
The proteinase inhibitor alpha-2-macroglobulin is found in association
with senile plaques in Alzheimer disease (AD; 104300). A2M has been
implicated biochemically in binding and degradation of the amyloid beta
protein which accumulates in senile plaques. In an initial exploratory
dataset (90 controls and 171 AD cases), Liao et al. (1998) noted an
increased frequency of the G/G genotype from 0.07 in controls to 0.12 in
AD. An additional independent dataset of 359 controls and 566 AD
patients were studied. In this hypothesis testing cohort, the G/G
genotype again increased from 0.07 in controls to 0.12 in AD. The odds
ratio for AD associated with the G/G genotype was 1.77 and in
combination with APOE4 (see 107741) was 9.68.
In a study of 148 patients from southern Italy with sporadic Alzheimer
disease, Zappia et al. (2004) found an increase in the val/val genotype
compared to controls, conferring an odds ratio of 3.58 for development
of the disease. In combination with a myeloperoxidase promoter
polymorphism genotype, -463G/G (606989.0008), the odds ratio increased
to 23.19. The authors suggested that the synergistic effect of the 2
genotypes may represent a facilitation of beta-amyloid deposition or a
decrease in amyloid clearance. The findings were independent of APOE4
status.
.0002
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, CYS972TYR
In 1 of 30 patients with chronic lung disease and in none of the 30
healthy persons studied by Poller et al. (1992), a mutation within the
thiolester site, changing cys972 (TGT) to tyr (TAT), was found. Since
activation of the internal thiolester formed between cys972 and gln975
in each of the subunits of the tetrameric A2M molecule is involved in
the covalent crosslinking of the activating proteinase, this mutation
was predicted to interfere with A2M function. The A2M serum level was
within the normal range in this patient.
.0003
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, IVS1DEL
In 1 healthy individual, Poller et al. (1992) found a deletion of the
intron that ordinarily separates exons 1 and 2. As a result, the 2 exons
that code the bait domain of the alpha-2-macroglobulin gene were fused.
.0004
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, ARG681HIS
Matthijs et al. (1992) demonstrated an amino acid polymorphism in the
bait domain of the alpha-2-macroglobulin molecule which defines the
specific interaction of the molecule with proteinases. A G-to-A
transition in exon 17 was detected in 1 person out of a group of 132
tested. The change predicted an arginine-to-his substitution at position
681. In the mutant allele an MaeII restriction site was lost and a new
NspHI site was created.
.0005
ALZHEIMER DISEASE, SUSCEPTIBILITY TO
A2M, EX18DEL
Matthijs and Marynen (1991) described a deletion polymorphism of the A2M
gene, a 5-prime splice site deletion in exon 18. This exon encodes 'exon
II' of the bait domain of alpha-2-microglobulin, which functions to
attract and trap proteases. Blacker et al. (1998) found that this
deletion, referred to as A2M-2, conferred increased risk for Alzheimer
disease (104300). The possibility increased risk for AD but without
modifying age of onset. It is possible that association of A2M-2 with AD
reflected linkage disequilibrium with another mutation in A2M or a
nearby gene.
.0006
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, 5-BP DEL
Matthijs and Marynen (1991) described a deletion polymorphism of the A2M
gene: 5 bases from -7 to -3 from the 5-prime splice site of exon 2.
Codominant segregation of the polymorphism was shown in 2 informative
families.
*FIELD* SA
Bell et al. (1985); David et al. (1987); Marynen et al. (1985)
*FIELD* RF
1. Anonymous: Freely associating. (Editorial) Nature Genet. 22:
1-2, 1999.
2. Bell, G. I.; Rall, L. B.; Sanchez-Pescador, R.; Merryweather, J.
P.; Scott, J.; Eddy, R. L.; Shows, T. B.: Human alpha-2-macroglobulin
gene is located on chromosome 12. Somat. Cell Molec. Genet. 11:
285-289, 1985.
3. Bergqvist, D.; Nilsson, I. M.: Hereditary alpha-2-macroglobulin
deficiency. Scand. J. Haemat. 23: 433-436, 1979.
4. Bian, L.; Yang, J. D.; Guo, T. W.; Duan, Y.; Qin, W.; Sun, Y.;
Feng, G. Y.; He, L.: Association study of the A2M and LRP1 genes
with Alzheimer disease in the Han Chinese. Biol. Psychiat. 58: 731-737,
2005.
5. Blacker, D.; Crystal, A. S.; Wilcox, M. A.; Laird, N. M.; Tanzi,
R. E.: Reply to Rudrasingham et al. (Letter) Nature Genet. 22:
21-22, 1999.
6. Blacker, D.; Wilcox, M. A.; Laird, N. M.; Rodes, L.; Horvath, S.
M.; Go, R. C. P.; Perry, R.; Watson, B., Jr.; Bassett, S. S.; McInnis,
M. G.; Albert, M. S.; Hyman, B. T.; Tanzi, R. E.: Alpha-2 macroglobulin
is genetically associated with Alzheimer disease. Nature Genet. 19:
357-360, 1998.
7. David, F.; Kan, C. C.; Lucotte, G.: Two Taq I RFLPs for human
alpha-2 macroglobulin (alpha-2M) using a full length cDNA probe. Nucleic
Acids Res. 15: 374 only, 1987.
8. Devriendt, K.; Zhang, J.; van Leuven, F.; van den Berghe, H.; Cassiman,
J. J.; Marynen, P.: A cluster of alpha 2-macroglobulin-related genes
(alpha 2 M) on human chromosome 12p: cloning of the pregnancy-zone
protein gene and an alpha 2M pseudogene. Gene 81: 325-334, 1989.
9. Dow, D. J.; Lindsey, N.; Cairns, N. J.; Brayne, C.; Robinson, D.;
Huppert, F. A.; Paykel, E. S.; Xuereb, J.; Wilcock, G.; Whittaker,
J. L.; Rubinsztein, D. C.: Alpha-2 macroglobulin polymorphism and
Alzheimer disease risk in the UK. (Letter) Nature Genet. 22: 16-17,
1999.
10. Flachsbart, F.; Caliebe, A.; Nothnagel, M.; Kleindorp, R.; Nikolaus,
S.; Schreiber, S.; Nebel, A.: Depletion of potential A2M risk haplotype
for Alzheimer's disease in long-lived individuals. Europ. J. Hum.
Genet. 18: 59-61, 2010.
11. Fukushima, Y.; Bell, G. I.; Shows, T. B.: The polymorphic human
alpha-2-macroglobulin gene (A2M) is located in chromosome region 12p12.3-p13.3. Cytogenet.
Cell Genet. 48: 58-59, 1988.
12. Gallango, M. L.; Castillo, O.: Alpha-2-macroglobulin polymorphism:
a new genetic system detected by immuno-electrophoresis. J. Immunogenet. 1:
147-151, 1974.
13. Hilliker, C.; Overbergh, L.; Petit, P.; Van Leuven, F.; Van den
Berghe, H.: Assignment of mouse alpha-2-macroglobulin gene to chromosome
6 band F1-G3. Mammalian Genome 3: 469-471, 1992.
14. Kan, C.-C.; Solomon, E.; Belt, K. T.; Chain, A. C.; Hiorns, L.
R.; Fey, G.: Nucleotide sequence of cDNA encoding human alpha-2-macroglobulin
and assignment of the chromosomal locus. Proc. Nat. Acad. Sci. 82:
2282-2286, 1985.
15. Leikola, J.; Fudenberg, H. H.; Kasukawa, R.; Milgrom, F.: A new
genetic polymorphism of human serum: alpha(2) macroglobulin (AL-M). Am.
J. Hum. Genet. 24: 134-144, 1972.
16. Liao, A.; Nitsch, R. M.; Greenberg, S. M.; Finckh, U.; Blacker,
D.; Albert, M.; Rebeck, G. W.; Gomez-Isla, T.; Clatworthy, A.; Binetti,
G.; Hock, C.; Mueller-Thomsen, T.; Mann, U.; Zuchowski, K.; Beisiegel,
U.; Staehelin, H.; Growdon, J. H.; Tanzi, R. E.; Hyman, B. T.: Genetic
association of an alpha-2-macroglobulin (val1000ile) polymorphism
and Alzheimer's disease. Hum. Molec. Genet. 7: 1953-1956, 1998.
17. Mantuano, E.; Mukandala, G.; Li, X.; Campana, W. M.; Gonias, S.
L.: Molecular dissection of the human alpha-2-macroglobulin subunit
reveals domains with antagonistic activities in cell signaling. J.
Biol. Chem. 283: 19904-19911, 2008.
18. Marynen, P.; Bell, G. I.; Cavalli-Sforza, L. L.: Three RFLPs
associated with the human alpha-2-macroglobulin gene (A2M). Nucleic
Acids Res. 13: 8287 only, 1985.
19. Marynen, P.; Zhang, J.; Devriendt, K.; Cassiman, J.-J.: Alpha-2-macroglobulin,
pregnancy zone protein and an alpha-2-macroglobulin pseudogene map
to chromosome 12p12.2-p13. (Abstract) Cytogenet. Cell Genet. 51:
1040 only, 1989.
20. Matthijs, G.; Devriendt, K.; Cassiman, J.-J.; van den Berghe,
H.; Marynen, P.: Structure of the human alpha-2 macroglobulin gene
and its promotor (sic). Biochem. Biophys. Res. Commun. 184: 596-603,
1992.
21. Matthijs, G.; Marynen, P.: A deletion polymorphism in the human
alpha-2-macroglobulin (A2M) gene. Nucleic Acids Res. 19: 5102 only,
1991.
22. Peslova, G.; Petrak, J.; Kuzelova, K.; Hrdy, I.; Halada, P.; Kuchel,
P. W.; Soe-Lin, S.; Ponka, P.; Sutak, R.; Becker, E.; Huang, M. L.-H.;
Rahmanto, Y. S.; Richardson, D. R.; Vyoral, D.: Hepcidin, the hormone
of iron metabolism, is bound specifically to alpha-2-macroglobulin
in blood. Blood 113: 6225-6236, 2009.
23. Poller, W.; Barth, J.; Voss, B.: Detection of an alteration of
the alpha-2-macroglobulin gene in a patient with chronic lung disease
and serum alpha-2-macroglobulin deficiency. Hum. Genet. 83: 93-96,
1989.
24. Poller, W.; Faber, J.-P.; Klobeck, G.; Olek, K.: Cloning of the
human alpha-2-macroglobulin gene and detection of mutations in two
functional domains: the bait region and the thiolester site. Hum.
Genet. 88: 313-319, 1992.
25. Rogaeva, E. A.; Premkumar, S.; Grubber, J.; Serneels, L.; Scott,
W. K.; Kawarai, T.; Song, Y.; Hill, D. M.; Abou-Donia, S. M.; Martin,
E. R.; Vance, J. J.; Yu, G.; and 18 others: An alpha-2-macroglobulin
insertion-deletion polymorphism in Alzheimer disease. (Letter) Nature
Genet. 22: 19-21, 1999.
26. Rudrasingham, V.; Wavrant-De Vrieze, F.; Lambert, J.-C.; Chakraverty,
S.; Kehoe, P.; Crook, R.; Amouyel, P.; Wu, W.; Rice, F.; Perez-Tur,
J.; Frigard, B.; Morris, J. C.; and 11 others: Alpha-2 macroglobulin
gene and Alzheimer disease. (Letter) Nature Genet. 22: 17-19, 1999.
27. Saunders, A. J.; Bertram, L.; Mullin, K.; Sampson, A. J.; Latifzai,
K.; Basu, S.; Jones, J.; Kinney, D.; MacKenzie-Ingano, L.; Yu, S.;
Albert, M. S.; Moscarillo, T. J.; and 10 others: Genetic association
of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin. Hum.
Molec. Genet. 12: 2765-2776, 2003.
28. Sottrup-Jensen, L.; Stepanik, T. M.; Kristensen, T.; Lonblad,
P. B.; Jones, C. M.; Wierzbicki, D. M.; Magnusson, S.; Domdey, H.;
Wetsel, R. A.; Lundwall, A.; Tack, B. F.; Fey, G. H.: Common evolutionary
origin of alpha-2-macroglobulin and complement components C3 and C4. Proc.
Nat. Acad. Sci. 82: 9-13, 1985.
29. Umans, L.; Serneels, L.; Hilliker, C.; Stas, L.; Overbergh, L.;
De Strooper, B.; Van Leuven, F.; Van den Berghe, H.: Molecular cloning
of the mouse gene coding for alpha-2-macroglobulin and targeting of
the gene in embryonic stem cells. Genomics 22: 519-529, 1994.
30. Umans, L.; Serneels, L.; Overbergh, L.; Lorent, K.; Van Leuven,
F.; Van den Berghe, H.: Targeted inactivation of the mouse alpha-2-macroglobulin
gene. J. Biol. Chem. 270: 19778-19785, 1995.
31. Webb, D. J.; Wen, J.; Lysiak, J. J.; Umans, L.; Van Leuven, F.;
Gonias, S. L.: Murine alpha-macroglobulins demonstrate divergent
activities as neutralizers of transforming growth factor-beta and
as inducers of nitric oxide synthesis: a possible mechanism for the
endotoxin insensitivity of the alpha-2-macroglobulin gene knock-out
mouse. J. Biol. Chem. 271: 24982-24988, 1996.
32. Zappia, M.; Manna, I.; Serra, P.; Cittadella, R.; Andreoli, V.;
La Russa, A.; Annesi, F.; Spadafora, P.; Romeo, N.; Nicoletti, G.;
Messina, D.; Gambardella, A.; Quattrone, A.: Increased risk for Alzheimer
disease with the interaction of MPO and A2M polymorphisms. Arch.
Neurol. 61: 341-344, 2004.
*FIELD* CN
Patricia A. Hartz - updated: 11/2/2010
Cassandra L. Kniffin - updated: 3/9/2010
John Logan Black, III - updated: 7/12/2006
George E. Tiller - updated: 1/31/2006
Cassandra L. Kniffin - updated: 6/16/2004
Cassandra L. Kniffin - reorganized: 1/17/2003
Victor A. McKusick - updated: 7/28/1999
Victor A. McKusick - updated: 4/27/1999
Victor A. McKusick - updated: 11/10/1998
Victor A. McKusick - updated: 8/13/1998
Victor A. McKusick - updated: 7/28/1998
Lori M. Kelman - updated: 6/3/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 06/09/2011
alopez: 11/10/2010
mgross: 11/5/2010
terry: 11/2/2010
carol: 5/25/2010
wwang: 4/7/2010
ckniffin: 3/9/2010
carol: 7/12/2006
terry: 7/12/2006
wwang: 2/9/2006
terry: 1/31/2006
tkritzer: 7/2/2004
ckniffin: 6/22/2004
ckniffin: 6/16/2004
mgross: 3/17/2004
carol: 1/17/2003
ckniffin: 1/8/2003
tkritzer: 12/23/2002
ckniffin: 12/18/2002
joanna: 4/3/2001
carol: 7/28/1999
alopez: 4/29/1999
terry: 4/27/1999
carol: 11/13/1998
terry: 11/10/1998
carol: 8/17/1998
terry: 8/13/1998
alopez: 7/31/1998
terry: 7/28/1998
terry: 11/21/1997
alopez: 6/3/1997
alopez: 4/4/1997
alopez: 4/1/1997
alopez: 3/21/1997
carol: 9/12/1994
mimadm: 3/11/1994
carol: 1/15/1993
carol: 6/19/1992
supermim: 3/16/1992
carol: 2/29/1992
*RECORD*
*FIELD* NO
103950
*FIELD* TI
*103950 ALPHA-2-MACROGLOBULIN; A2M
;;MACROGLOBULIN, ALPHA-2
*FIELD* TX
DESCRIPTION
read more
A2M is a 718-kD homotetrameric glycoprotein of plasma and extracellular
spaces that was first recognized as a broad spectrum protease inhibitor.
A2M is activated by proteases with which it interacts, and this
proteolytic activation causes a conformational change that traps the
protease within the A2M homotetramer. In addition, A2M contains several
independent domains that function as carriers of specific growth factors
and/or binding sites for receptors. Activation of A2M by proteases
alters the interaction of A2M with these ligands and induces cell
signaling (summary by Mantuano et al., 2008).
CLONING
Using synthetic oligonucleotides as hybridization probes, Kan et al.
(1985) isolated A2M cDNA clones from a human liver cDNA library. The
coding sequence predicted a 1,451-amino acid polypeptide. Human A2M is a
tetramer of 4 identical 185-kD subunits arranged as a pair of dimers,
each consisting of 2 disulfide-linked monomers. The protein has a bait
region composed of peptide bonds for plasma proteases and a thiol ester
bond which, when hydrolyzed, leads to covalent bonding between the
protease and A2M.
GENE STRUCTURE
Matthijs et al. (1992) demonstrated that the A2M gene spans
approximately 48 kb and consists of 36 exons, from 21 to 229 bp in size
and with consensus splice sites. Intron sizes range from 125 bp to 7.5
kb. The A2M gene is present in single copy in the haploid genome. Umans
et al. (1994) found that the homologous gene in the mouse contains 36
exons, coding for a 4.8-kb cDNA. Including putative control elements in
the 5-prime flanking region, the gene covers about 45 kb. The promoter
region of the mouse A2m gene differed considerably from the known
promoter sequences of the human and rat genes.
MAPPING
Kan et al. (1985) assigned the A2M locus to chromosome 12 by Southern
blot analysis of DNA from a panel of mouse/human somatic cell hybrids,
using A2M cDNA as a hybridization probe. Fukushima et al. (1988)
assigned the A2M locus to 12p13.3-p12.3 by in situ hybridization.
Assignment of the A2M gene to human chromosome 12p13-p12.2 was confirmed
by Marynen et al. (1989) by use of in situ hybridization and somatic
cell hybrid DNA analysis. Devriendt et al. (1989) also assigned A2M to
12p13-p12 by analysis of somatic cell hybrids and in situ hybridization.
They showed, furthermore, that a closely related gene for pregnancy-zone
protein (PZP; 176420) and an A2M pseudogene map to the same region.
Hilliker et al. (1992) showed that the gene is located on mouse
chromosome 6 band F1-G3 in a syntenic group that has its human
counterpart on 12p13-p12.
GENE FUNCTION
Alpha-2-macroglobulin is, like alpha-1-antitrypsin, alpha-2-antiplasmin,
and antithrombin III, a protease inhibitor. It inhibits many proteases,
including trypsin, thrombin, and collagenase (Bergqvist and Nilsson,
1979).
Mantuano et al. (2008) used isolated recombinant human A2M protein
fragments, which they called FP3 and FP6, to characterize the cellular
functions of specific A2M domains. FP3 contains residues 591 to 774 of
A2M and includes the growth factor carrier sites, and FP6 contains
residues 1242 to 1451 of A2M and includes the LRP1 (107770) recognition
domain. FP6 rapidly and robustly activated Akt (see 164730) and Erk/MAP
kinases (see 176948) in cultured rat Schwann cells and PC12 rat
pheochromocytoma cells. FP6 also promoted neurite outgrowth and
expression of Gap43 (162060). These cell signaling events were mediated
by Lrp1 and depended on 2 lysines in FP6 that were required for Lrp1
binding. The ability of FP6 to trigger Lrp1-dependent cell signaling in
PC12 cells was reproduced by a purified 18-kD fragment of human plasma
A2M that included the LRP1 recognition domain. FP3 alone did not induce
cell signaling in rat Schwann and PC12 cells, but it blocked Ngf-beta
(NGFB; 162030)-induced activation of Akt and Erk/MAP kinases. FP3 did
not block activation of cell signaling induced by FP6.
Using mass spectrometry, Peslova et al. (2009) showed that hepcidin
(HAMP; 606464) in human plasma or serum was bound by albumin (ALB;
103600) and by A2M. Binding of hepcidin to albumin was nonspecific and
displayed nonsaturable kinetics. However, binding of hepcidin to A2M was
specific. Scatchard analysis estimated 2 hepcidin-binding sites per
inactive A2M molecule. Proteolytic activation of A2M resulted in a
sigmoidal binding curve, suggesting high-affinity cooperative allosteric
binding of 4 hepcidin molecules per active A2M molecule. The
hepcidin-A2M complex, but not the hepcidin-albumin complex, decreased
ferroportin (SLC40A1; 604653) expression in J774 murine macrophages more
effectively than hepcidin alone. Peslova et al. (2009) hypothesized that
A2M has a role in regulating hepcidin action by sequestration and
subsequent release.
MOLECULAR GENETICS
- Alpha-2-Macroglobulin Deficiency
By the electroimmunoassay of Laurell, Bergqvist and Nilsson (1979) found
alpha-2-macroglobulin deficiency (614036) in a 37-year-old man, his
mother, and one daughter. The deficient persons were apparently
heterozygotes. No clinical disadvantage resulted from the deficiency.
Poller et al. (1989) detected an alteration in the A2M gene in a patient
with serum A2M deficiency and chronic lung disease since childhood. The
alteration involved restriction sites detected with 10 different enzymes
and was thought to have been caused by major deletion or rearrangement
in the gene. Nine of the restriction enzymes used detected no
polymorphism in 40 healthy control subjects and 39 patients with chronic
obstructive pulmonary disease. The patient was heterozygous for the A2M
alteration; Poller et al. (1989) suggested that this was responsible for
the pulmonary disease.
- Association with Alzheimer Disease
Alpha-2-macroglobulin has been implicated in Alzheimer disease (AD;
104300) based on its ability to mediate the clearance and degradation of
A-beta, the major component of amyloid beta deposits. Blacker et al.
(1998) analyzed a deletion in the A2M gene (103950.0005) at the 5-prime
splice site of 'exon II' of the bait region (exon 18) and found that
inheritance of the deletion, designated A2M-2, conferred increased risk
for AD (Mantel-Haenzel odds ratio = 3.56, P = 0.001). The sibship
disequilibrium test (SDT) also revealed a significant association
between A2M and AD. These values were comparable to those obtained for
the APOE4 allele in the same sample, but in contrast to APOE4, A2M-2 did
not affect age of onset. The observed association that A2M with AD did
not appear to account for the previously published linkage of AD to
chromosome 12, which Blacker et al. (1998) were unable to confirm in
their sample. Thus, A2M, the A2M receptor (LRP1; 107770), and the genes
for 2 other LRP (low density lipoprotein-related protein) ligands, APOE
(107741) and APP (104760), had all been genetically linked to AD,
suggesting that these proteins may participate in the common
neuropathogenic pathway leading to the disease. Liao et al. (1998) found
an association between the val1000-to-ile polymorphism (103950.0001) and
AD.
In a study of AD in 3 samples of patients in the U.K., Dow et al. (1999)
failed to show a strong association between A2M-2 and AD risk.
Rudrasingham et al. (1999) did not find associations between AD and
A2M-2, or genotypes containing A2M-2, in a powerful, case-control
sample. Using the same family-based association methods employed by
Blacker et al. (1998), Rogaeva et al. (1999) also could not replicate
the association of A2M-2 in 2 comparable, independent familial AD
datasets or in a larger dataset of families from the same dataset tested
by Blacker et al. (1998). Furthermore, they were unable to document any
biologic effect of the A2M-2 allele on A2M RNA splicing, protein
monomeric molecular mass, or protein levels in brain, liver, or plasma
of A2M-2 carriers. Rogaeva et al. (1999) concluded that prior genetic
evidence for an AD susceptibility locus on chromosome 12 likely arose
from genetic variations other than in A2M-2 alleles. In a reply to these
criticisms, Blacker et al. (1999) commented that they did not find it
surprising that the case-control studies conducted by the groups of
Rudrasingham et al. (1999), Rogaeva et al. (1999), and Dow et al. (1999)
could not find an association. They suggested that the findings
highlighted differences between family-based and case-control
association studies. In an accompanying editorial (Anonymous, 1999), the
editor of Nature Genetics pointed out the difficulties in evaluating the
results of association studies. Unresolved fundamental issues included
such matters as the significance threshold of a true association
(especially in light of multiple-hypothesis testing aggravated by
publication bias for positive associations), how best to analyze a given
dataset, and what constitutes a valid refutation. The editors suggested
that they would expect manuscripts reporting genetic associations to
include an estimate of the effect size and to contain either a
replication in an independent sample or physiologically meaningful data
supporting a functional role of the polymorphism in question.
Saunders et al. (2003) resequenced the A2M locus and identified 7 novel
polymorphisms to test for genetic association with AD. Using the full
NIMH sample of 1,439 individuals in 437 families, they found significant
genetic association of the 5-bp deletion (103950.0005) and 2 novel
polymorphisms with AD. Substantial linkage disequilibrium was detected
across the gene as a whole, and haplotype analysis also showed
significant association between AD and groups of A2M polymorphisms.
Several of these polymorphisms and haplotypes remained significantly
associated with AD even after correction for multiple testing. The data
supported a potential role for A2M or a nearby gene in AD.
Bian et al. (2005) found no association of 6 A2M gene polymorphisms
(5-prime UTR A/G, dbSNP rs226379; T/G, dbSNP rs226380, intron 6 A/C;
exon 24 A/G; intron 27 A/G; intron 34 T/C, dbSNP rs3759277) with AD in a
study of 216 late-onset AD patients and 200 control subjects from the
Han Chinese population. Comparison of allele, genotype, and haplotype
frequencies for polymorphisms in A2M revealed no significant differences
between patients and control subjects.
Flachsbart et al. (2010) found that an A2M risk haplotype for Alzheimer
disease, comprising dbSNP rs3832852 and dbSNP rs669, was significantly
less frequent among 1,042 long-lived German individuals, aged 95 to 100
years, without AD compared to 1,040 younger German individuals, aged 60
to 75 years, without AD. The results suggested that the haplotype is a
mortality factor in the elderly. The findings were independent of APOE
status.
EVOLUTION
From comparison of the sequence of the subunit of human
alpha-2-macroglobulin with those of C3 (120700) and C4 (120810, 120820),
Sottrup-Jensen et al. (1985) concluded that these 3 proteins, which all
contain a unique activatable beta-cysteinyl-gamma-glutamyl thiol ester,
have a common evolutionary origin. C5 (120900) also shows sequence
homology to A2M.
ANIMAL MODEL
Umans et al. (1995) created mice lacking the alpha-2-macroglobulin gene.
The knockout mice were not only viable, but more resistant to endotoxin.
They produced normal-sized litters and showed no obvious phenotypic
abnormalities. Webb et al. (1996) demonstrated that murine
alpha-2-macroglobulin binds TGF-beta and inhibits TGF-beta-receptor
interactions. They suggested that these results explain the
endotoxin-insensitive phenotype of the knockout mice.
HISTORY
Leikola et al. (1972) identified an antigenic material of a high
molecular weight that they termed alpha-2-macroglobulin. They detected a
polymorphism in Japanese persons that was distinct from the Gm locus,
which determines the serologic type of gamma immunoglobulin (see
147100), the Am locus, which determines the serologic type of alpha
immunoglobulin (see 146900 and 147000), and haptoglobins (140100). It
was likewise distinct from Xm (314900), also a macroglobulin, as
indicated by the autosomal inheritance and specific tests. Gene
frequency of the allele whose product was demonstrated by the antiserum
was about 0.16 in Japanese. Using a rabbit antihuman serum, Gallango and
Castillo (1974) also described a polymorphism of alpha-2-macroglobulin.
This may be separate from that described by Leikola et al. (1972).
*FIELD* AV
.0001
ALPHA-2-MACROGLOBULIN POLYMORPHISM
ALZHEIMER DISEASE, SUSCEPTIBILITY TO, INCLUDED
A2M, VAL1000ILE
By direct genomic sequencing of the 2 exons encoding the bait region and
the exon encoding the thiolester site in 30 healthy individuals and in
30 patients with chronic lung disease, Poller et al. (1992) found a
sequence polymorphism near the thiolester site of the gene, changing
val1000 (GTC) to ile (ATC); the 2 alleles had frequencies of 0.30 and
0.70, respectively. No difference of A2M serum levels was observed for
these 2 alleles.
The proteinase inhibitor alpha-2-macroglobulin is found in association
with senile plaques in Alzheimer disease (AD; 104300). A2M has been
implicated biochemically in binding and degradation of the amyloid beta
protein which accumulates in senile plaques. In an initial exploratory
dataset (90 controls and 171 AD cases), Liao et al. (1998) noted an
increased frequency of the G/G genotype from 0.07 in controls to 0.12 in
AD. An additional independent dataset of 359 controls and 566 AD
patients were studied. In this hypothesis testing cohort, the G/G
genotype again increased from 0.07 in controls to 0.12 in AD. The odds
ratio for AD associated with the G/G genotype was 1.77 and in
combination with APOE4 (see 107741) was 9.68.
In a study of 148 patients from southern Italy with sporadic Alzheimer
disease, Zappia et al. (2004) found an increase in the val/val genotype
compared to controls, conferring an odds ratio of 3.58 for development
of the disease. In combination with a myeloperoxidase promoter
polymorphism genotype, -463G/G (606989.0008), the odds ratio increased
to 23.19. The authors suggested that the synergistic effect of the 2
genotypes may represent a facilitation of beta-amyloid deposition or a
decrease in amyloid clearance. The findings were independent of APOE4
status.
.0002
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, CYS972TYR
In 1 of 30 patients with chronic lung disease and in none of the 30
healthy persons studied by Poller et al. (1992), a mutation within the
thiolester site, changing cys972 (TGT) to tyr (TAT), was found. Since
activation of the internal thiolester formed between cys972 and gln975
in each of the subunits of the tetrameric A2M molecule is involved in
the covalent crosslinking of the activating proteinase, this mutation
was predicted to interfere with A2M function. The A2M serum level was
within the normal range in this patient.
.0003
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, IVS1DEL
In 1 healthy individual, Poller et al. (1992) found a deletion of the
intron that ordinarily separates exons 1 and 2. As a result, the 2 exons
that code the bait domain of the alpha-2-macroglobulin gene were fused.
.0004
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, ARG681HIS
Matthijs et al. (1992) demonstrated an amino acid polymorphism in the
bait domain of the alpha-2-macroglobulin molecule which defines the
specific interaction of the molecule with proteinases. A G-to-A
transition in exon 17 was detected in 1 person out of a group of 132
tested. The change predicted an arginine-to-his substitution at position
681. In the mutant allele an MaeII restriction site was lost and a new
NspHI site was created.
.0005
ALZHEIMER DISEASE, SUSCEPTIBILITY TO
A2M, EX18DEL
Matthijs and Marynen (1991) described a deletion polymorphism of the A2M
gene, a 5-prime splice site deletion in exon 18. This exon encodes 'exon
II' of the bait domain of alpha-2-microglobulin, which functions to
attract and trap proteases. Blacker et al. (1998) found that this
deletion, referred to as A2M-2, conferred increased risk for Alzheimer
disease (104300). The possibility increased risk for AD but without
modifying age of onset. It is possible that association of A2M-2 with AD
reflected linkage disequilibrium with another mutation in A2M or a
nearby gene.
.0006
ALPHA-2-MACROGLOBULIN POLYMORPHISM
A2M, 5-BP DEL
Matthijs and Marynen (1991) described a deletion polymorphism of the A2M
gene: 5 bases from -7 to -3 from the 5-prime splice site of exon 2.
Codominant segregation of the polymorphism was shown in 2 informative
families.
*FIELD* SA
Bell et al. (1985); David et al. (1987); Marynen et al. (1985)
*FIELD* RF
1. Anonymous: Freely associating. (Editorial) Nature Genet. 22:
1-2, 1999.
2. Bell, G. I.; Rall, L. B.; Sanchez-Pescador, R.; Merryweather, J.
P.; Scott, J.; Eddy, R. L.; Shows, T. B.: Human alpha-2-macroglobulin
gene is located on chromosome 12. Somat. Cell Molec. Genet. 11:
285-289, 1985.
3. Bergqvist, D.; Nilsson, I. M.: Hereditary alpha-2-macroglobulin
deficiency. Scand. J. Haemat. 23: 433-436, 1979.
4. Bian, L.; Yang, J. D.; Guo, T. W.; Duan, Y.; Qin, W.; Sun, Y.;
Feng, G. Y.; He, L.: Association study of the A2M and LRP1 genes
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*FIELD* CN
Patricia A. Hartz - updated: 11/2/2010
Cassandra L. Kniffin - updated: 3/9/2010
John Logan Black, III - updated: 7/12/2006
George E. Tiller - updated: 1/31/2006
Cassandra L. Kniffin - updated: 6/16/2004
Cassandra L. Kniffin - reorganized: 1/17/2003
Victor A. McKusick - updated: 7/28/1999
Victor A. McKusick - updated: 4/27/1999
Victor A. McKusick - updated: 11/10/1998
Victor A. McKusick - updated: 8/13/1998
Victor A. McKusick - updated: 7/28/1998
Lori M. Kelman - updated: 6/3/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 06/09/2011
alopez: 11/10/2010
mgross: 11/5/2010
terry: 11/2/2010
carol: 5/25/2010
wwang: 4/7/2010
ckniffin: 3/9/2010
carol: 7/12/2006
terry: 7/12/2006
wwang: 2/9/2006
terry: 1/31/2006
tkritzer: 7/2/2004
ckniffin: 6/22/2004
ckniffin: 6/16/2004
mgross: 3/17/2004
carol: 1/17/2003
ckniffin: 1/8/2003
tkritzer: 12/23/2002
ckniffin: 12/18/2002
joanna: 4/3/2001
carol: 7/28/1999
alopez: 4/29/1999
terry: 4/27/1999
carol: 11/13/1998
terry: 11/10/1998
carol: 8/17/1998
terry: 8/13/1998
alopez: 7/31/1998
terry: 7/28/1998
terry: 11/21/1997
alopez: 6/3/1997
alopez: 4/4/1997
alopez: 4/1/1997
alopez: 3/21/1997
carol: 9/12/1994
mimadm: 3/11/1994
carol: 1/15/1993
carol: 6/19/1992
supermim: 3/16/1992
carol: 2/29/1992