Reviewed, UniProtKB/Swiss-Prot P01023 (A2MG_HUMAN)

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

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.

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]

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 space Inferred from electronic annotation. Source: InterPro nucleus Inferred from direct assay. Source: HPA platelet alpha granule lumen Inferred from Experiment. Source: Reactome
Molecular function	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 serine-type endopeptidase inhibitor activity Inferred from electronic annotation. Source: UniProtKB-KW tumor necrosis factor binding Inferred from direct assay. Source: UniProtKB wide-spectrum protease inhibitor activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 23

23

Chain

24 – 1474

1451

Alpha-2-macroglobulin

PRO_0000000055

Regions

Region

690 – 728

39

Bait region

Region

704 – 709

6

Inhibitory

Region

719 – 723

5

Inhibitory

Region

730 – 735

6

Inhibitory

Amino acid modifications

Glycosylation

55

1

N-linked (GlcNAc...)

Glycosylation

70

1

N-linked (GlcNAc...)

Glycosylation

247

1

N-linked (GlcNAc...)

Glycosylation

396

1

N-linked (GlcNAc...)

Glycosylation

410

1

N-linked (GlcNAc...)

Glycosylation

869

1

N-linked (GlcNAc...)

Glycosylation

991

1

N-linked (GlcNAc...)

Glycosylation

1424

1

N-linked (GlcNAc...)

Disulfide bond

48 ↔ 86

Disulfide bond

251 ↔ 299

Disulfide bond

269 ↔ 287

Disulfide bond

278

Interchain (with C-431)

Disulfide bond

431

Interchain (with C-278)

Disulfide bond

470 ↔ 563

Disulfide bond

595 ↔ 771

Disulfide bond

642 ↔ 689

Disulfide bond

821 ↔ 849

Disulfide bond

847 ↔ 883

Disulfide bond

921 ↔ 1321

Disulfide bond

1079 ↔ 1127

Disulfide bond

1352 ↔ 1467

Cross-link

693

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

1

D → N: dbSNP rs226405.

VAR_026820

Natural variant

704

1

R → H: dbSNP rs1800434.

VAR_000012

Natural variant

815

1

L → Q: dbSNP rs3180392.

VAR_026821

Natural variant

972

1

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

VAR_000013

Natural variant

1000

1

V → I: dbSNP rs669.

VAR_000014

Experimental info

Sequence conflict

63

1

Missing AA sequence Ref.7

Sequence conflict

82

1

D → V in AAT02228. Ref.3

Sequence conflict

350 – 353

4

LSFV → ACCS in AAH26246. Ref.6

Sequence conflict

563

1

C → E AA sequence Ref.7

Sequence conflict

844

1

A → V in BAD92851. Ref.5

Sequence conflict

872

1

V → M in CAH18188. Ref.4

Sequence conflict

1148

1

A → D in AAA51552. Ref.12

Sequence conflict

1195

1

H → D in AAA51552. Ref.12

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

1474

Helix Strand Turn

Details...

Beta strand

1341 – 1347

7

Helix

1355 – 1359

5

Beta strand

1360 – 1369

10

Beta strand

1379 – 1384

6

Beta strand

1389 – 1391

3

Helix

1393 – 1400

8

Turn

1401 – 1403

3

Beta strand

1407 – 1410

4

Beta strand

1412 – 1419

8

Beta strand

1427 – 1434

8

Beta strand

1445 – 1450

6

Beta strand

1454 – 1456

3

Beta strand

1459 – 1463

5

Sequences

	Sequence		Length	Mass (Da)
	P01023-1 [UniParc]. Last modified August 13, 1987. Version 1. Checksum: F1D517427971CEFE	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

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. , Wu Q.Y., Qiang B.Q., Yuan J.G., Liew C.C., Zhao M.S., 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]