Cooperation of N- and C-terminal substrate transmembrane domain segments in intramembrane proteolysis by γ-secretase

Nadine T. Werner, Philipp Högel, Gökhan Güner, Walter Stelzer, Manfred Wozny, Marlene Aßfalg, Stefan F. Lichtenthaler, Harald Steiner, Dieter Langosch

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Intramembrane proteases play a pivotal role in biology and medicine, but how these proteases decode cleavability of a substrate transmembrane (TM) domain remains unclear. Here, we study the role of conformational flexibility of a TM domain, as determined by deuterium/hydrogen exchange, on substrate cleavability by γ-secretase in vitro and in cellulo. By comparing hybrid TMDs based on the natural amyloid precursor protein TM domain and an artificial poly-Leu non-substrate, we find that substrate cleavage requires conformational flexibility within the N-terminal half of the TMD helix (TM-N). Robust cleavability also requires the C-terminal TM sequence (TM-C) containing substrate cleavage sites. Since flexibility of TM-C does not correlate with cleavage efficiency, the role of the TM-C may be defined mainly by its ability to form a cleavage-competent state near the active site, together with parts of presenilin, the enzymatic component of γ-secretase. In sum, cleavability of a γ-secretase substrate appears to depend on cooperating TM domain segments, which deepens our mechanistic understanding of intramembrane proteolysis.

Original languageEnglish
Article number177
JournalCommunications Biology
Volume6
Issue number1
DOIs
StatePublished - Dec 2023

Fingerprint

Dive into the research topics of 'Cooperation of N- and C-terminal substrate transmembrane domain segments in intramembrane proteolysis by γ-secretase'. Together they form a unique fingerprint.

Cite this