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

Academic Article

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. © 2011 Elsevier Inc.
  • Digital Object Identifier (doi)

    Author List

  • Wang X; Cowan JW; Gerhart M; Zelickson BR; Jiang J; He K; Wolfe MS; Black RA; Frank SJ
  • Start Page

  • 432
  • End Page

  • 436
  • Volume

  • 408
  • Issue

  • 3