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  • Title: γ-Secretase-mediated growth hormone receptor proteolysis: mapping of the intramembranous cleavage site.
    Author: Wang X, Cowan JW, Gerhart M, Zelickson BR, Jiang J, He K, Wolfe MS, Black RA, Frank SJ.
    Journal: Biochem Biophys Res Commun; 2011 May 13; 408(3):432-6. PubMed ID: 21514282.
    Abstract:
    GH receptor (GHR) undergoes regulated proteolysis by both metalloprotease (α-secretase) and γ-secretase activities. α-Secretase activity regulates GHR availability and sensitivity and generates circulating GH binding protein. The function of γ-secretase cleavage is yet uncertain. We investigated GHR determinants that affect inducible sequential α- and γ-secretase cleavage and thus remnant and stub generation, respectively. Purification and N-terminal sequencing of the stub revealed that γ-secretase cleavage occurs at an ε-site in GHR's transmembrane domain four residues from the intracellular domain. Mutagenesis revealed that deletion of the proximal two transmembrane residues prevented both α- and γ-secretase-mediated proteolysis and deletion of four residues around the ε-site precluded surface GHR expression and proteolysis. However, point mutations in and around the ε-site affected neither α- or γ-secretase cleavage. We conclude that both cleavages likely occur at the cell surface and sequentially (α-secretase followed by γ-secretase) and that ε-site cleavage by γ-secretase does not require a consensus sequence.
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