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alpha-2-macroglobulin; alpha-2-M; C3 & PZP-like alpha-2-macroglobulin domain-containing protein 5 (A2M, CPAMD5, FWP007)

Function: - binds proteases - alpha-2 Macroglobulin contributes more than 1/4 of the thrombin inhibition normally present in plasma - when alpha-2 macroglobulin reacts with proteinase, it undergoes a major conformational change that has been termed protease trapping - protease trapping is accompanied by hydrolysis of a gamma-glutamyl Cys & activation of alpha-2 macroglobulin - activated alpha-2 macrogloblulin is the ligand for the alpha-2 macroglobulin receptor LRP - the alpha-2 macroglobulin/Receptor complex may provide a mechanism for protease clearance - able to inhibit all four classes of proteinases trapping mechanism Structure: - homotetramer; disulfide-linked - belongs to the protease inhibitor I39 (alpha-2-macroglobulin) family - peptide stretch, called the 'bait region' contains specific cleavage sites for different proteinases Compartment: secreted Expression: - secreted in plasma - contrary to the rat protein, which is an acute phase protein, this protein is always present at high levels in circulation Pathology: - it has been proposed that a common isoform of the gene for alpha-2 macroglobulin increases risk of Alzheimer's disease [4] - plasma levels are elevated in a) nephrotic syndrome b) protein-losing gastroenteropathies c) hepatic cirrhosis d) diabetes mellitus Laboratory: - serum protein electrophoresis - alpha-2 Macroglobulin normally accounts for 25% of the alpha-2 band - its large size contributes to selective retention on the gel

Interactions

molecular events

Related

alpha-2-macroglobulin in serum alpha-2-macroglobulin-like protein 1 (C3 & PZP-like alpha-2-macroglobulin domain-containing protein 9, A2ML1, CPAMD9) alpha-2-macroglobulin/total protein in serum CD91, low density lipoprotein (LDL) receptor related protein (LRP) 1, apolipoprotein E [apoE] receptor 1, chylomicron remnant receptor or alpha-2 macroglobulin receptor

General

acute phase protein alpha 2 globulin macroglobulin oligomerizing protein protease inhibitor regulatory molecule sialoglycoprotein

Properties

CONFIGURATION: tetramer SIZE: MW = 725 kD COMPARTMENT: plasma MOTIF: proteolytic site glycosylation site MODIFICATION: sialic acid cysteine residue {C949} MODIFICATION: glutamate residue {E952} glutamate residue {E952} MODIFICATION: cysteine residue {C949} binding site EFFECTOR-BOUND: insulin for injection binding site FOR-BINDING-OF: serine protease INHIBITS: thrombin trypsin plasmin pepsin kallikrein STATE: Inactive MISC-INFO: CONCENTRATION 150-350 MG/DL

Database Correlations

OMIM 103950 UniProt P01023 PFAM correlations Kegg hsa:2

References

  1. Clinical Diagnosis & Management by Laboratory Methods, J.B. Henry (ed), W.B. Saunders Co., Philadelphia, PA. 1991, pg 222
  2. Clinical Chemistry, Principles, Procedures, Correlations, 2nd ed., Bishop, Duben-Engelkirk, Fody (eds), JB Lippincott, Philadelphia, 1991 pg 184
  3. Wolf BB et al Characterization and immunohistochemical localization of alpha 2-macroglobulin receptor (low-density lipoprotein receptor-related protein) in human brain. Am J Pathol 141:37 1992 PMID: 1632469
  4. Blacker D et al Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet. 1998 Aug;19(4):357-60. PMID: 9697696
  5. Entrez Gene :accession 2
  6. UniProt :accession P01023
  7. Wikipedia; Note: alpha-2 macroglobulin entry http://en.wikipedia.org/wiki/alpha_2-macroglobulin

Component-of

molecular complex