Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/15153
Título
Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α2-macroglobulin
Autor(es)
Fecha de publicación
2022-05-10
Cita
Proc Natl Acad Sci USA. 2022 May 10;119(19):e2200102119.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
Palabras clave
Conformational states | Multifunctional complex | Blood proteostasis | Proteinase | α2-macroglobulin
MESH
Peptide Hydrolases | alpha-Macroglobulins | Cryoelectron Microscopy | Endopeptidases | Humans | Protein Conformation | Transcription Factors
Descripción
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.
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