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

Werner, Nadine T. T.; Hoegel, Philipp; Guener, Gokhan; Stelzer, Walter; Wozny, Manfred; Assfalg, Marlene; Lichtenthaler, Stefan F.; Steiner, Harald und Langosch, Dieter (2023): Cooperation of N- and C-terminal substrate transmembrane domain segments in intramembrane proteolysis by γ-secretase. In: Communications Biology, Bd. 6, Nr. 1, 177

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 gamma-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 gamma-secretase. In sum, cleavability of a gamma-secretase substrate appears to depend on cooperating TM domain segments, which deepens our mechanistic understanding of intramembrane proteolysis. Deuterium/hydrogen exchange shows that conformational flexibility of the hybrid transmembrane domains (TMD) of amyloid precursor proteins plays a role in TMD cleavability by gamma-secretase in vitro and in cellulo.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198