dc.contributor.author | Luque, Daniel | |
dc.contributor.author | Goulas, Theodoros | |
dc.contributor.author | Mata, Carlos P | |
dc.contributor.author | Mendes, Soraia R | |
dc.contributor.author | Gomis-Rüth, F Xavier | |
dc.contributor.author | Castón, José R | |
dc.date.accessioned | 2022-11-15T13:41:58Z | |
dc.date.available | 2022-11-15T13:41:58Z | |
dc.date.issued | 2022-05-10 | |
dc.identifier.citation | Proc Natl Acad Sci USA. 2022 May 10;119(19):e2200102119. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/15153 | |
dc.description | Correction: 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. | es_ES |
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. | es_ES |
dc.description.sponsorship | This work was supported by grants from the Spanish Ministries of Economy and Competitivity (Grant No. BFU2017-88736-R) and of Science and Innovation (Grant No. PID2020-113287RB-I00) and the Comunidad Autónoma de Madrid (Grant No. P2018/NMT-4389) to J.R.C. and by grants from Catalan and Spanish public and private agencies (Grant Nos. BFU2019-107725-RB-I00 and 2017SGR00003; Fundacio “La Marat o de TV3” Grant No. 201815) to F.X.G.-R. T.G. acknowledges a Juan de la Cierva research contract (JCI-2012-13573) from the Ministry of Economy (MINECO) and S.R.M. a Ph.D.-fellowship (BES2016-076877) from the Ministry of Science and Innovation. The Structural Biology Unit of the Molecular Biology Institute of Barcelona (IBMB) was a María de Maeztu Unit of Excellence (2015 to 2019) and the Centro Nacional de Biotecnología is a Severo Ochoa Center of Excellence (MINECO award SEV 2017-0712), as awarded by the Spanish Ministry of Economy, Industry and Competitiveness. The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | National Academy of Sciences | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Conformational states | es_ES |
dc.subject | Multifunctional complex | es_ES |
dc.subject | Blood proteostasis | es_ES |
dc.subject | Proteinase | es_ES |
dc.subject | α2-macroglobulin | es_ES |
dc.subject.mesh | Peptide Hydrolases | es_ES |
dc.subject.mesh | alpha-Macroglobulins | es_ES |
dc.subject.mesh | Cryoelectron Microscopy | es_ES |
dc.subject.mesh | Endopeptidases | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Protein Conformation | es_ES |
dc.subject.mesh | Transcription Factors | es_ES |
dc.title | Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α2-macroglobulin | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.identifier.pubmedID | 35500114 | es_ES |
dc.format.volume | 119 | es_ES |
dc.format.number | 19 | es_ES |
dc.format.page | e2200102119 | es_ES |
dc.identifier.doi | 10.1073/pnas.2200102119 | es_ES |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.contributor.funder | Fundación La Marató TV3 | es_ES |
dc.contributor.funder | Ministerio de Economía (España) | es_ES |
dc.contributor.funder | Molecular Biology Institute of Barcelona (España) | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.contributor.funder | Ministerio de Economía, Industria y Competitividad (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1091-6490 | es_ES |
dc.identifier.journal | Proceedings of the National Academy of Sciences of the United States of America | es_ES |
dc.repisalud.centro | ISCIII::Centro Nacional de Microbiología | es_ES |
dc.repisalud.institucion | ISCIII | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BFU2017-88736-R | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2020-113287RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/JCI-2012-13573 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BES2016-076877 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SEV2017-0712 | es_ES |