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Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis.
eLife 11:e76090 (2022)
Cleavage of membrane proteins in the lipid bilayer by intramembrane proteases is crucial for health and disease. Although different lipid environments can potently modulate their activity, how this is linked to their structural dynamics is unclear. Here we show that the carboxy-peptidase-like activity of the archaeal intramembrane protease PSH, a homolog of the Alzheimer's disease-associated presenilin/γ-secretase is impaired in micelles and promoted in a lipid bilayer. Comparative molecular dynamics simulations revealed that important elements for substrate binding such as transmembrane domain 6a of PSH are more labile in micelles and stabilized in the lipid bilayer. Moreover, consistent with an enhanced interaction of PSH with a transition-state analog inhibitor, the bilayer promoted the formation of the enzyme´s catalytic active site geometry. Our data indicate that the lipid environment of an intramembrane protease plays a critical role in structural stabilization and active site arrangement of the enzyme-substrate complex thereby promoting intramembrane proteolysis.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Biochemistry ; Chemical Biology ; Molecular Biophysics ; None ; Structural Biology
ISSN (print) / ISBN
2050-084X
e-ISSN
2050-084X
Zeitschrift
eLife
Quellenangaben
Band: 11,
Artikelnummer: e76090
Verlag
eLife Sciences Publications
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
CF Monoclonal Antibodies (CF-MAB)
Förderungen
Deutsche Forschungsgemeinschaft