dc.creator | Luque D., Goulas T., Mata C.P., Mendes S.R., Gomis-Rüth F.X., Castón J.R. | en |
dc.date.accessioned | 2023-01-31T08:55:31Z | |
dc.date.available | 2023-01-31T08:55:31Z | |
dc.date.issued | 2022 | |
dc.identifier | 10.1073/pnas.2200102119 | |
dc.identifier.issn | 00278424 | |
dc.identifier.uri | http://hdl.handle.net/11615/76029 | |
dc.description.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. Copyright © 2022 the Author(s). | en |
dc.language.iso | en | en |
dc.source | Proceedings of the National Academy of Sciences of the United States of America | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85129781794&doi=10.1073%2fpnas.2200102119&partnerID=40&md5=bafcf53a9f5af138fb2f9c3e8c449a48 | |
dc.subject | alpha 2 macroglobulin | en |
dc.subject | plasma protein | en |
dc.subject | proteinase | en |
dc.subject | tetramer | en |
dc.subject | thioester | en |
dc.subject | peptide hydrolase | en |
dc.subject | transcription factor | en |
dc.subject | Article | en |
dc.subject | bait region domain | en |
dc.subject | controlled study | en |
dc.subject | covalent bond | en |
dc.subject | cryoelectron microscopy | en |
dc.subject | internalization (cell) | en |
dc.subject | protein degradation | en |
dc.subject | protein domain | en |
dc.subject | protein homeostasis | en |
dc.subject | receptor binding | en |
dc.subject | receptor binding domain | en |
dc.subject | thioester domain | en |
dc.subject | chemistry | en |
dc.subject | cryoelectron microscopy | en |
dc.subject | human | en |
dc.subject | metabolism | en |
dc.subject | protein conformation | en |
dc.subject | alpha-Macroglobulins | en |
dc.subject | Cryoelectron Microscopy | en |
dc.subject | Endopeptidases | en |
dc.subject | Humans | en |
dc.subject | Peptide Hydrolases | en |
dc.subject | Protein Conformation | en |
dc.subject | Transcription Factors | en |
dc.subject | National Academy of Sciences | en |
dc.title | Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α2-macroglobulin | en |
dc.type | journalArticle | en |