ArticleNature communications2022
Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 13 citations in OpenAlex.
- Human α2-Macroglobulin: Architecture, Mechanisms, and Functional Implications.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Review
- Antagonist nanobodies prevent protease inhibition by CD109.The Journal of biological chemistry · 2026Article
- Multi-omics integration and machine learning uncover molecular basal-like subtype of pancreatic cancer and implicate A2ML1 in promoting tumor epithelial-mesenchymal transition.Journal of translational medicine · 2025Article
- Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring.Nature structural & molecular biology · 2025Article
- Engineering New Protease Inhibitors Using αMethods in molecular biology (Clifton, N.J.) · 2024Article
- Audiologic Measures in an Indigenous Community withGenetic testing and molecular biomarkers · 2023Article
- Recent cryogenic electron microscopy structures of human A2M may not be representative of the native protein.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A2ML1 is a monomeric protease inhibitor belonging to the A2M superfamily of protease inhibitors and complement factors. Here, we investigate the protease-inhibitory mechanism of human A2ML1 and determine the structures of its native and protease-cleaved conformations. The functional inhibitory unit of A2ML1 is a monomer that depends on covalent binding of the protease (mediated by A2ML1's thioester) to achieve inhibition. In contrast to the A2M tetramer which traps proteases in two internal chambers formed by four subunits, in protease-cleaved monomeric A2ML1 disordered regions surround the trapped protease and may prevent substrate access. In native A2ML1, the bait region is threaded through a hydrophobic channel, suggesting that disruption of this arrangement by bait region cleavage triggers the extensive conformational changes that result in protease inhibition. Structural comparisons with complement C3/C4 suggest that the A2M superfamily of proteins share this mechanism for the triggering of conformational change occurring upon proteolytic activation.
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