PT  - JOURNAL ARTICLE
AU  - Lukas P. Feilen
AU  - Shu-Yu Chen
AU  - Akio Fukumori
AU  - Regina Feederle
AU  - Martin Zacharias
AU  - Harald Steiner
TI  - Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis
AID  - 10.1101/2022.01.10.475655
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.10.475655
4099  - http://biorxiv.org/content/early/2022/01/10/2022.01.10.475655.short
4100  - http://biorxiv.org/content/early/2022/01/10/2022.01.10.475655.full
AB  - 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 Alzheimeŕs 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 enzymés 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.Competing Interest StatementThe authors have declared no competing interest.