Alpha-2-macroglobulin precursor - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot P01023 (A2MG_HUMAN)

Last modified July 22, 2008. Version 113. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Alpha-2-macroglobulin
      Short name=Alpha-2-M
Alternative name(s):
    C3 and PZP-like alpha-2-macroglobulin domain-containing protein 5

Gene names

Name:	A2M
Synonyms:	CPAMD5
ORF Names:	FWP007

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	1474 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Is able to inhibit all four classes of proteinases by a unique 'trapping' mechanism. This protein has 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 which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates (activity against high molecular weight substrates is greatly reduced). Following cleavage in the bait region a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase.
Subunit structure	Homotetramer; disulfide-linked.
Subcellular location	Secreted.
Tissue specificity	Plasma.
Developmental stage	Contrary to the rat protein, which is an acute phase protein, this protein is always present at high levels in circulation.
Sequence similarities	Belongs to the protease inhibitor I39 (alpha-2-macroglobulin) family. [View classification]

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Ontologies

Keywords
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Domain	Bait region Signal
Molecular function	Protease inhibitor Serine protease inhibitor
PTM	Glycoprotein Thioester bond
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	protein homooligomerization Non-traceable author statement. Source: UniProtKB
Cellular component	extracellular region Non-traceable author statement. Source: UniProtKB platelet alpha granule lumen Inferred from Experiment. Source: Reactome
Molecular function	endopeptidase inhibitor activity Non-traceable author statement. Source: UniProtKB enzyme binding Inferred from physical interaction. Source: UniProtKB interleukin-1 binding Inferred from direct assay. Source: UniProtKB interleukin-8 binding Inferred from physical interaction. Source: UniProtKB tumor necrosis factor binding Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Signal peptide

1 – 23

Chain

24 – 1474

1451

Alpha-2-macroglobulin

Regions

Region

690 – 728

Bait region

Region

704 – 709

Inhibitory

Region

719 – 723

Inhibitory

Region

730 – 735

Inhibitory

Amino acid modifications

Glycosylation

N-linked (GlcNAc...)

Glycosylation

N-linked (GlcNAc...)

Glycosylation

247

N-linked (GlcNAc...)

Glycosylation

396

N-linked (GlcNAc...)

Glycosylation

410

N-linked (GlcNAc...)

Glycosylation

869

N-linked (GlcNAc...)

Glycosylation

991

N-linked (GlcNAc...)

Glycosylation

1424

N-linked (GlcNAc...)

Disulfide bond

Disulfide bond

Disulfide bond

Disulfide bond

Interchain (with C-431)

Disulfide bond

431

Interchain (with C-278)

Disulfide bond

Disulfide bond

Disulfide bond

Disulfide bond

Disulfide bond

Disulfide bond

Disulfide bond

Disulfide bond

Cross-link

Isoglutamyl lysine isopeptide (Gln-Lys) (interchain with K-? in other proteins) Potential

Cross-link

694

Isoglutamyl lysine isopeptide (Gln-Lys) (interchain with K-? in other proteins) Potential

Cross-link

972 ↔ 975

Isoglutamyl cysteine thioester (Cys-Gln)

Natural variations

Natural variant

639

D → N: dbSNP rs226405.

Natural variant

704

R → H: dbSNP rs1800434.

Natural variant

815

L → Q: dbSNP rs3180392.

Natural variant

972

C → Y Probably interferes with the activity. dbSNP rs1800433.

Natural variant

1000

V → I: dbSNP rs669.

Experimental info

Sequence conflict

Missing AA sequence Ref.7

Sequence conflict

D → V in AAT02228. Ref.3

Sequence conflict

350 – 353

LSFV → ACCS in AAH26246. Ref.6

Sequence conflict

563

C → E AA sequence Ref.7

Sequence conflict

844

A → V in BAD92851. Ref.5

Sequence conflict

872

V → M in CAH18188. Ref.4

Sequence conflict

1148

A → D in AAA51552. Ref.12

Sequence conflict

1195

H → D in AAA51552. Ref.12

Secondary structure

1474

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P01023-1 [UniParc].

Last modified August 13, 1987. Version 1.
Checksum: F1D517427971CEFE
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FASTA

1,474

163,278

        10         20         30         40         50         60 
MGKNKLLHPS LVLLLLVLLP TDASVSGKPQ YMVLVPSLLH TETTEKGCVL LSYLNETVTV 

        70         80         90        100        110        120 
SASLESVRGN RSLFTDLEAE NDVLHCVAFA VPKSSSNEEV MFLTVQVKGP TQEFKKRTTV 

       130        140        150        160        170        180 
MVKNEDSLVF VQTDKSIYKP GQTVKFRVVS MDENFHPLNE LIPLVYIQDP KGNRIAQWQS 

       190        200        210        220        230        240 
FQLEGGLKQF SFPLSSEPFQ GSYKVVVQKK SGGRTEHPFT VEEFVLPKFE VQVTVPKIIT 

       250        260        270        280        290        300 
ILEEEMNVSV CGLYTYGKPV PGHVTVSICR KYSDASDCHG EDSQAFCEKF SGQLNSHGCF 

       310        320        330        340        350        360 
YQQVKTKVFQ LKRKEYEMKL HTEAQIQEEG TVVELTGRQS SEITRTITKL SFVKVDSHFR 

       370        380        390        400        410        420 
QGIPFFGQVR LVDGKGVPIP NKVIFIRGNE ANYYSNATTD EHGLVQFSIN TTNVMGTSLT 

       430        440        450        460        470        480 
VRVNYKDRSP CYGYQWVSEE HEEAHHTAYL VFSPSKSFVH LEPMSHELPC GHTQTVQAHY 

       490        500        510        520        530        540 
ILNGGTLLGL KKLSFYYLIM AKGGIVRTGT HGLLVKQEDM KGHFSISIPV KSDIAPVARL 

       550        560        570        580        590        600 
LIYAVLPTGD VIGDSAKYDV ENCLANKVDL SFSPSQSLPA SHAHLRVTAA PQSVCALRAV 

       610        620        630        640        650        660 
DQSVLLMKPD AELSASSVYN LLPEKDLTGF PGPLNDQDDE DCINRHNVYI NGITYTPVSS 

       670        680        690        700        710        720 
TNEKDMYSFL EDMGLKAFTN SKIRKPKMCP QLQQYEMHGP EGLRVGFYES DVMGRGHARL 

       730        740        750        760        770        780 
VHVEEPHTET VRKYFPETWI WDLVVVNSAG VAEVGVTVPD TITEWKAGAF CLSEDAGLGI 

       790        800        810        820        830        840 
SSTASLRAFQ PFFVELTMPY SVIRGEAFTL KATVLNYLPK CIRVSVQLEA SPAFLAVPVE 

       850        860        870        880        890        900 
KEQAPHCICA NGRQTVSWAV TPKSLGNVNF TVSAEALESQ ELCGTEVPSV PEHGRKDTVI 

       910        920        930        940        950        960 
KPLLVEPEGL EKETTFNSLL CPSGGEVSEE LSLKLPPNVV EESARASVSV LGDILGSAMQ 

       970        980        990       1000       1010       1020 
NTQNLLQMPY GCGEQNMVLF APNIYVLDYL NETQQLTPEV KSKAIGYLNT GYQRQLNYKH 

      1030       1040       1050       1060       1070       1080 
YDGSYSTFGE RYGRNQGNTW LTAFVLKTFA QARAYIFIDE AHITQALIWL SQRQKDNGCF 

      1090       1100       1110       1120       1130       1140 
RSSGSLLNNA IKGGVEDEVT LSAYITIALL EIPLTVTHPV VRNALFCLES AWKTAQEGDH 

      1150       1160       1170       1180       1190       1200 
GSHVYTKALL AYAFALAGNQ DKRKEVLKSL NEEAVKKDNS VHWERPQKPK APVGHFYEPQ 

      1210       1220       1230       1240       1250       1260 
APSAEVEMTS YVLLAYLTAQ PAPTSEDLTS ATNIVKWITK QQNAQGGFSS TQDTVVALHA 

      1270       1280       1290       1300       1310       1320 
LSKYGAATFT RTGKAAQVTI QSSGTFSSKF QVDNNNRLLL QQVSLPELPG EYSMKVTGEG 

      1330       1340       1350       1360       1370       1380 
CVYLQTSLKY NILPEKEEFP FALGVQTLPQ TCDEPKAHTS FQISLSVSYT GSRSASNMAI 

      1390       1400       1410       1420       1430       1440 
VDVKMVSGFI PLKPTVKMLE RSNHVSRTEV SSNHVLIYLD KVSNQTLSLF FTVLQDVPVR 

      1450       1460       1470 
DLKPAIVKVY DYYETDEFAI AEYNAPCSKD LGNA

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Nucleotide sequence of cDNA encoding human alpha 2-macroglobulin and assignment of the chromosomal locus." Kan C.-C., Solomon E., Belt K.T., Chain A.C., Hiorns L.R., Fey G.H. Proc. Natl. Acad. Sci. U.S.A. 82:2282-2286(1985) [PubMed: 2581245] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Structure of the human alpha-2 macroglobulin gene and its promotor." Matthijs G., Devriendt K., Cassiman J.-J., van den Berghe H., Marynen P. Biochem. Biophys. Res. Commun. 184:596-603(1992) [PubMed: 1374237] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT HIS-704. Tissue: Placenta.
[3]	"Alpha(2) macroglobulin, a PSA-binding protein, is expressed in human prostate stroma." Lin V.K., Wang S.-Y., Boetticher N.C., Vazquez D.V., Saboorian H., McConnell J.D., Roehrborn C.G. Prostate 63:299-308(2005) [PubMed: 15611997] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Prostate.
[4]	The German cDNA consortium Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Liver.
[5]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno F.R. Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ILE-1000. Tissue: Spleen.
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Skin.
[7]	"Primary structure of human alpha 2-macroglobulin. V. The complete structure." Sottrup-Jensen L., Stepanik T.M., Kristensen T., Wierzbicki D.M., Jones C.M., Loenblad P.B., Magnusson S., Petersen T.E. J. Biol. Chem. 259:8318-8327(1984) [PubMed: 6203908] [Abstract] Cited for: PROTEIN SEQUENCE OF 24-1474, SUBUNIT, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DISULFIDE BONDS.
[8]	Erratum Sottrup-Jensen L., Stepanik T.M., Kristensen T., Wierzbicki D.M., Jones C.M., Loenblad P.B., Magnusson S., Petersen T.E. J. Biol. Chem. 260:6500-6500(1985)
[9]	"Primary structure of human alpha 2-macroglobulin. Complete disulfide bridge assignment and localization of two interchain bridges in the dimeric proteinase binding unit." Jensen P.E.H., Sottrup-Jensen L. J. Biol. Chem. 261:15863-15869(1986) [PubMed: 2430963] [Abstract] Cited for: PROTEIN SEQUENCE OF 273-286 AND 426-436, DISULFIDE BONDS.
[10]	"A genetic polymorphism in a functional domain of human pregnancy zone protein: the bait region. Genomic structure of the bait domains of human pregnancy zone protein and alpha 2 macroglobulin." Marynen P., Devriendt K., van den Berghe H., Cassiman J.-J. FEBS Lett. 262:349-352(1990) [PubMed: 1692292] [Abstract] Cited for: PROTEIN SEQUENCE OF 672-747.
[11]	"Cloning of the human alpha 2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site." Poller W., Faber J.-P., Klobeck G., Olek K. Hum. Genet. 88:313-319(1992) [PubMed: 1370808] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 672-746, VARIANTS TYR-972 AND ILE-1000.
[12]	"Human alpha 2-macroglobulin gene is located on chromosome 12." Bell G.I., Rall L.B., Sanchez-Pescador R., Merryweather J.P., Scott J., Eddy R.L., Shows T.B. Somat. Cell Mol. Genet. 11:285-289(1985) [PubMed: 2408344] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 832-1474. Tissue: Liver.
[13]	Liu B., Zhao B., Wang X.Y., Xu Y.Y., Liu Y.Q., Song L., Ye J., Sheng H., Gao Y., Zhang C.L., Wei Y.J., Zhang J., Song L., Jiang Y.X., Zhao Z.W., Ding J.F., Liu L.S., Gao R.L. Hui R.T. Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1208-1474. Tissue: Aorta.
[14]	"Proteolytic cleavage sites on alpha 2-macroglobulin resulting in proteinase binding are different for trypsin and Staphylococcus aureus V-8 proteinase." Hall P.K., Nelles L.P., Travis J., Roberts R.C. Biochem. Biophys. Res. Commun. 100:8-16(1981) [PubMed: 6167263] [Abstract] Cited for: INHIBITORY SITE.
[15]	"Primary structure of the 'bait' region for proteinases in alpha 2-macroglobulin. Nature of the complex." Sottrup-Jensen L., Loenblad P.B., Stepanik T.M., Petersen T.E., Magnusson S., Joernvall H. FEBS Lett. 127:167-173(1981) [PubMed: 6165619] [Abstract] Cited for: INHIBITORY SITE.
[16]	"Primary and secondary cleavage sites in the bait region of alpha 2-macroglobulin." Mortensen S.B., Sottrup-Jensen L., Hansen H.F., Petersen T.E., Magnusson S. FEBS Lett. 135:295-300(1981) [PubMed: 6172288] [Abstract] Cited for: INHIBITORY SITE.
[17]	"Human neutrophil elastase and cathepsin G cleavage sites in the bait region of alpha 2-macroglobulin. Proposed structural limits of the bait region." Virca G.D., Salvesen G.S., Travis J. Hoppe-Seyler's Z. Physiol. Chem. 364:1297-1302(1983) [PubMed: 6195065] [Abstract] Cited for: INHIBITORY SITE.
[18]	"Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry." Zhang H., Li X.-J., Martin D.B., Aebersold R. Nat. Biotechnol. 21:660-666(2003) [PubMed: 12754519] [Abstract] Cited for: GLYCOSYLATION AT ASN-991.
[19]	"Screening for N-glycosylated proteins by liquid chromatography mass spectrometry." Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R. Proteomics 4:454-465(2004) [PubMed: 14760718] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-869 AND ASN-1424, MASS SPECTROMETRY. Tissue: Plasma.
[20]	"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry." Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D. J. Proteome Res. 4:2070-2080(2005) [PubMed: 16335952] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-55; ASN-247; ASN-396; ASN-410; ASN-869; ASN-991 AND ASN-1424, MASS SPECTROMETRY. Tissue: Plasma.
[21]	"Localization of basic residues required for receptor binding to the single alpha-helix of the receptor binding domain of human alpha2-macroglobulin." Huang W., Dolmer K., Liao X., Gettins P.G.W. Protein Sci. 7:2602-2612(1998) [PubMed: 9865955] [Abstract] Cited for: STRUCTURE BY NMR OF 1337-1474.
[22]	"Human alpha2-macroglobulin is composed of multiple domains, as predicted by homology with complement component C3." Doan N., Gettins P.G.W. Biochem. J. 407:23-30(2007) [PubMed: 17608619] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 126-227, DOMAIN STRUCTURE.
[23]	"Sequence polymorphism in the human alpha2-macroglobulin (A2M) gene." Poller W., Faber J.-P., Olek K. Nucleic Acids Res. 19:198-198(1991) [PubMed: 1707161] [Abstract] Cited for: VARIANT ILE-1000.
+	Additional computationally mapped references.

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Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Sequence annotation (Features)

Molecule processing

Regions

Amino acid modifications

Natural variations

Experimental info

Secondary structure

Sequences

References