PROSITE documentation PDOC00440
Alpha-2-macroglobulin family thiolester region signature


The proteinase-binding α-macroglobulins (A2M) [1] are large glycoproteins found in the plasma of vertebrates, in the hemolymph of some invertebrates and in reptilian and avian egg white. A2M-like proteins are able to inhibit all four classes of proteinases by a 'trapping' mechanism. They have a peptide stretch, called the 'bait region', which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein, thus trapping the proteinase. The entrapped enzyme remains active against low molecular weight substrates, whilst its activity toward larger substrates is greatly reduced, due to steric hindrance. Following cleavage in the bait region, a thiol ester bond, formed between the side chains of a cysteine and a glutamine, is cleaved and mediates the covalent binding of the A2M-like protein to the proteinase.

The proteins which are known to belong to this family are:

  • α-2-macroglobulin from mammals, lobster, and crayfish.
  • α-1-inhibitor III from rat.
  • Pregnancy zone protein (PZP) from human.
  • Ovostatin from birds.
  • Complement components C3, C4 and C5. These proteins do not inhibit proteinases. C3 plays a central role in the activation of both classical and alternative complement pathways. After C3 is cleaved to form C3b, it can bind covalently, via its reactive thiol ester bond, to cell surface carbohydrates or immune aggregates. Similarily C4, once activated to C4b, can bind to various molecules.

As a signature pattern for this family of proteins, we have selected the region containing the two residues involved in the thiol ester bond.

Expert(s) to contact by email:

van Leuven F.

Last update:

May 1991 / First entry.


Technical section

PROSITE method (with tools and information) covered by this documentation:

ALPHA_2_MACROGLOBULIN, PS00477; Alpha-2-macroglobulin family thiolester region signature  (PATTERN)


1AuthorsSottrup-Jensen L.
TitleAlpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation.
SourceJ. Biol. Chem. 264:11539-11542(1989).
PubMed ID2473064

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