Structure of a bacterial α2-macroglobulin reveals mimicry of eukaryotic innate immunity

Nat Commun. 2014 Sep 15:5:4917. doi: 10.1038/ncomms5917.


Alpha-2-macroglobulins (A2Ms) are plasma proteins that trap and inhibit a broad range of proteases and are major components of the eukaryotic innate immune system. Surprisingly, A2M-like proteins were identified in pathogenically invasive bacteria and species that colonize higher eukaryotes. Bacterial A2Ms are located in the periplasm where they are believed to provide protection to the cell by trapping external proteases through a covalent interaction with an activated thioester. Here we report the crystal structures and characterization of Salmonella enterica ser. Typhimurium A2M in different states of thioester activation. The structures reveal thirteen domains whose arrangement displays high similarity to proteins involved in eukaryotic immune defence. A structural lock mechanism maintains the stability of the buried thioester, a requirement for its protease-trapping activity. These findings indicate that bacteria have developed a rudimentary innate immune system whose mechanism mimics that of eukaryotes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology
  • Crystallography, X-Ray
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Esters
  • Gene Expression
  • Humans
  • Models, Molecular
  • Molecular Mimicry
  • Molecular Sequence Data
  • Peptide Hydrolases / chemistry*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Salmonella typhimurium / chemistry*
  • Salmonella typhimurium / immunology
  • Sequence Homology, Amino Acid
  • Tyrosine / chemistry
  • alpha-Macroglobulins / chemistry*
  • alpha-Macroglobulins / genetics
  • alpha-Macroglobulins / immunology


  • Bacterial Proteins
  • Esters
  • Recombinant Proteins
  • alpha-Macroglobulins
  • Tyrosine
  • Peptide Hydrolases

Associated data

  • PDB/4U48
  • PDB/4U4J
  • PDB/4U59