Structural Mechanics of the Alpha-2-Macroglobulin Transformation

J Mol Biol. 2022 Mar 15;434(5):167413. doi: 10.1016/j.jmb.2021.167413. Epub 2021 Dec 20.


Alpha-2-Macroglobulin (A2M) is the critical pan-protease inhibitor of the innate immune system. When proteases cleave the A2M bait region, global structural transformation of the A2M tetramer is triggered to entrap the protease. The structural basis behind the cleavage-induced transformation and the protease entrapment remains unclear. Here, we report cryo-EM structures of native- and intermediate-forms of the Xenopus laevis egg A2M homolog (A2Moo or ovomacroglobulin) tetramer at 3.7-4.1 Å and 6.4 Å resolution, respectively. In the native A2Moo tetramer, two pairs of dimers arrange into a cross-like configuration with four 60 Å-wide bait-exposing grooves. Each bait in the native form threads into an aperture formed by three macroglobulin domains (MG2, MG3, MG6). The bait is released from the narrowed aperture in the induced protomer of the intermediate form. We propose that the intact bait region works as a "latch-lock" to block futile A2M transformation until its protease-mediated cleavage.

Keywords: Xenopus egg extract; alpha-2-macroglobulin; cryo-EM; innate immunity; protein inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cryoelectron Microscopy
  • Peptide Hydrolases / chemistry
  • Protein Conformation
  • Protein Multimerization
  • Proteolysis*
  • Transcription Factors* / chemistry
  • Xenopus Proteins* / chemistry
  • alpha-Macroglobulins* / chemistry


  • A2M protein, Xenopus
  • Transcription Factors
  • Xenopus Proteins
  • alpha-Macroglobulins
  • ovomacroglobulin
  • Peptide Hydrolases