The transmembrane domain of Frey1 harbors a transplantable inhibitory motif for intramembrane proteases

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Although aspartic intramembrane-cleaving proteases (I-CLIPs) are crucial switches of multiple signaling pathways and involved in several devastating diseases, little is known about their physiological regulation. We have recently identified Frey regulator of sperm-oocyte fusion 1 (Frey1) as an inhibitory protein of Signal Peptide Peptidase-like 2c (SPPL2c), a member of this protease family. Employing structure modeling along with cell-based inhibition and interaction studies, we identify a short motif within the Frey1 transmembrane domain essential for inhibition of SPPL2c. Intriguingly, this motif can be transplanted to the SPPL2c substrate PLN, thereby transforming it into an inhibitor of this enzyme. It can be adopted for the generation of Notch1-based γ-Secretase inhibitors demonstrating its versatile use among aspartic I-CLIPs. In summary, we describe a mechanism of aspartic I-CLIP inhibition which allows the targeted generation of specific inhibitors of these enzymes and might enable the identification of endogenous negative regulators of these enzymes.


Original languageEnglish
Pages (from-to)170
JournalCellular and Molecular Life Sciences
Issue number6
Publication statusPublished - 1 Jun 2023

External IDs

PubMedCentral PMC10234869
Scopus 85160958047



  • Male, Animals, Membrane Proteins/metabolism, Proteolysis, Semen/metabolism, Aspartic Acid Endopeptidases/metabolism, Peptide Hydrolases/metabolism, Amyloid Precursor Protein Secretases/genetics