Structural highlights
Function
[A2MG_HUMAN] 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.
Publication Abstract from PubMed
SignificanceHuman alpha2-macroglobulin (halpha2M) is an approximately 720-kDa homotetrameric particle with pan-peptidase inhibitory functions that transits between an open native conformation and a closed induced state, in which endopeptidases are trapped upon cleavage of an accessible bait region. We determined the molecular mechanism of this function through eight cryo-electron microscopy (cryo-EM) structures, which revealed that the halpha2M subunits are organized in two flexible modules that undergo independent expanded-to-compact transitions. In the induced state, a reactive thioester bond triggers covalent linking of the proteinase, and a receptor-binding domain is exposed on the tetramer surface for binding to its specific cellular receptor for internalization and clearance from circulation. These results elucidate the long-awaited molecular mechanism of a historical suicidal inhibitory trap.
Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human alpha2-macroglobulin.,Luque D, Goulas T, Mata CP, Mendes SR, Gomis-Ruth FX, Caston JR Proc Natl Acad Sci U S A. 2022 May 10;119(19):e2200102119. doi:, 10.1073/pnas.2200102119. Epub 2022 May 2. PMID:35500114[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Luque D, Goulas T, Mata CP, Mendes SR, Gomis-Ruth FX, Caston JR. Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human alpha2-macroglobulin. Proc Natl Acad Sci U S A. 2022 May 10;119(19):e2200102119. doi:, 10.1073/pnas.2200102119. Epub 2022 May 2. PMID:35500114 doi:http://dx.doi.org/10.1073/pnas.2200102119
