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oai:repisalud.isciii.es:20.500.12105/151532024-09-27T23:52:04Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19609

00925njm 22002777a 4500 dc Luque, Daniel author Goulas, Theodoros author Mata, Carlos P author Mendes, Soraia R author Gomis-Rüth, F Xavier author Castón, José R author 2022-05-10 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. Proc Natl Acad Sci USA. 2022 May 10;119(19):e2200102119. 10.1073/pnas.2200102119 1091-6490 Proceedings of the National Academy of Sciences of the United States of America 35500114 http://hdl.handle.net/20.500.12105/15153 Conformational states Multifunctional complex Blood proteostasis Proteinase α2-macroglobulin Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α2-macroglobulin