Luque, DanielGoulas, TheodorosMata, Carlos PMendes, Soraia RGomis-Rüth, F XavierCastón, José R2022-11-152022-11-152022-05-10Proc Natl Acad Sci USA. 2022 May 10;119(19):e2200102119.http://hdl.handle.net/20.500.12105/15153Correction: Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α2-macroglobulin. Proc Natl Acad Sci USA. 2022 Jun 14;119(24):e2208467119. doi: 10.1073/pnas.2208467119. PMID: 35671431.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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Conformational statesMultifunctional complexBlood proteostasisProteinaseα2-macroglobulinPeptide Hydrolasesalpha-MacroglobulinsCryoelectron MicroscopyEndopeptidasesHumansProtein ConformationTranscription FactorsAttribution-NonCommercial-NoDerivatives 4.0 Internacional3550011411919e220010211910.1073/pnas.22001021191091-6490Proceedings of the National Academy of Sciences of the United States of Americaopen access