Intramembrane cleavage of Alcadein proteins by γ-secretase

Saori Hata, Toshiharu Suzuki

Laboratory of Neuroscience, Faculty of Pharmaceutical Sciences, Hokkaido University

Alcadein (Alc) family are type I membrane proteins and predominantly expressed in neurons, as is amyloid-β protein precursor (APP). Both Alcs and APP are primary cleaved by α- or β-secretase to generate C-terminal fragments (CTFs). APP and Alc CTFs are further cleaved by γ-secretase to secrete Aβ or p3 peptide from APP and p3-Alc peptides from Alc along with the release of intracellular domain fragments (ICD). In the case of γ-secretase cleavage of APP, the initial ε-site is thought to define the final γ-site position. However, unlike APP, the relationship between ε-site and γ-site positions in the cleavage of Alcs by γ-secretase is not rigid. We summarize the molecular mechanism of γ-secretase cleavage of Alc protein.

Address correspondence to Saori Hata, Laboratory of Neuroscience, Faculty of Pharmaceutical Sciences, Hokkaido University (Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan)