ArticleProceedings of the National Academy of Sciences of the United States of America2022
Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 12 papers.
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Who cites it
12 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
- Isolation and Endopeptidase Inhibition of Human α 2-Macroglobulin.Methods in molecular biology (Clifton, N.J.) · 2026Article
- The CAGE complex: a hollow, megadalton, protein assembly in prokaryotic and eukaryotic microbes.bioRxiv : the preprint server for biology · 2025Article
- Dissecting Cytophagalysin: Structural and Biochemical Studies of a Bacterial Pappalysin-Family Metallopeptidase.Biomolecules · 2024Article
- Validation of electron-microscopy maps using solution small-angle X-ray scattering.Acta crystallographica. Section D, Structural biology · 2024Article
- Alpha 2-macroglobulin acts as a clearance factor in the lysosomal degradation of extracellular misfolded proteins.Scientific reports · 2023Article
- Frozen fresh blood plasma preserves the functionality of native human αScientific reports · 2023Article
- Quantifying In Situ Structural Stabilities of Human Blood Plasma Proteins Using a Novel Iodination Protein Stability Assay.Journal of proteome research · 2022Article
- Cryo-EM structures reveal the dynamic transformation of human alpha-2-macroglobulin working as a protease inhibitor.Science China. Life sciences · 2022Article
- Reply to Harwood et al.: Alternative functional conformations of native human αProceedings of the National Academy of Sciences of the United States of America · 2022Article
- 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
- Structural and evolutionary insights into astacin metallopeptidases.Frontiers in molecular biosciences · 2022Article
Corrections and comments
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Authors and funding
6 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human α2-macroglobulin (hα2M) is a multidomain protein with a plethora of essential functions, including transport of signaling molecules and endopeptidase inhibition in innate immunity. Here, we dissected the molecular mechanism of the inhibitory function of the ∼720-kDa hα2M tetramer through eight cryo–electron microscopy (cryo-EM) structures of complexes from human plasma. In the native complex, the hα2M subunits are organized in two flexible modules in expanded conformation, which enclose a highly porous cavity in which the proteolytic activity of circulating plasma proteins is tested. Cleavage of bait regions exposed inside the cavity triggers rearrangement to a compact conformation, which closes openings and entraps the prey proteinase. After the expanded-to-compact transition, which occurs independently in the four subunits, the reactive thioester bond triggers covalent linking of the proteinase, and the receptor-binding domain is exposed on the tetramer surface for receptor-mediated clearance from circulation. These results depict the molecular mechanism of a unique suicidal inhibitory trap.
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