γ-Secretase-mediated growth hormone receptor proteolysis: Mapping of the intramembranous cleavage site

► We investigated GHR determinants of sequential α- and γ-secretase cleavage. ► γ-Secretase cleavage occurs at a transmembrane domain ε-site. ► Deletion of two proximal transmembrane residues prevents α-/γ-secretase proteolysis. ► Deletion of four ε-site residues prevents surface expression and proteolysis. ► Point mutations in and around the ε-site did not affect α-/γ-secretase cleavage.