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Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α2-macroglobulin

Luque, Daniel ; Goulas, Theodoros ; Mata, Carlos P ; Mendes, Soraia R ; Gomis-Rüth, F Xavier ; Castón, José R

Proceedings of the National Academy of Sciences - PNAS, 2022-05, Vol.119 (19), p.1-e2200102119 [Periódico revisado por pares]

Washington: National Academy of Sciences

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  • Título:
    Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α2-macroglobulin
  • Autor: Luque, Daniel ; Goulas, Theodoros ; Mata, Carlos P ; Mendes, Soraia R ; Gomis-Rüth, F Xavier ; Castón, José R
  • Assuntos: Baits ; Biological Sciences ; Blood plasma ; Electron microscopy ; Endopeptidase ; Innate immunity ; Peptidase ; Peptidases ; Plasma proteins ; Prey ; Proteinase ; Proteins ; Proteolysis ; Receptors
  • É parte de: Proceedings of the National Academy of Sciences - PNAS, 2022-05, Vol.119 (19), p.1-e2200102119
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    Edited by Robert Huber, Max Planck Institute of Biochemistry, Planegg-Martinsried, Germany; received January 4, 2022; accepted March 28, 2022
    2Present address: Spanish National Microbiology Centre, Institute of Health Carlos III, 28220 Madrid, Spain.
    1D.L., T.G., and C.P.M. contributed equally to this work.
    Author contributions: F.X.G.-R. and J.R.C. designed research; D.L., T.G., C.P.M., S.R.M., and F.X.G.-R. performed research; D.L. and T.G. analyzed data; and F.X.G.-R. and J.R.C. wrote the paper.
  • Descrição: 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.
  • Editor: Washington: National Academy of Sciences
  • Idioma: Inglês
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