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

Cell Mol Life Sci. 2023 Jun 1;80(6):170. doi: 10.1007/s00018-023-04823-7.


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.

Keywords: Alzheimer’s disease; Enzyme inhibitors; Intramembrane proteolysis; Protease regulation; Signal peptide peptidase-like proteases; γ-Secretase.

MeSH terms

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


  • Membrane Proteins
  • Aspartic Acid Endopeptidases
  • Peptide Hydrolases
  • Amyloid Precursor Protein Secretases