The GxxxG motif in the transmembrane domain of AβPP plays an essential role in the interaction of CTFβ with the γ-secretase complex and the formation of amyloid-β

gamma-secretase-mediated processing of the amyloid-beta protein precursor (A beta PP) is a crucial step in the formation of the amyloid-beta peptide (A beta), but little is known about how the substrate A beta PP interacts with the gamma-secretase complex. To understand the molecular events involved in gamma-secretase-mediated A beta PP processing and A beta formation, in the present study we determined the role of a well conserved GxxxG motif in the transmembrane domain of A beta PP. Our data clearly demonstrate that substitution of aspartic acid for the key glycine residues in the GxxxG motif almost completely abolished the formation of A beta. Furthermore, our data revealed that substitution of aspartic acid for the glycine in this GxxxG motif disrupts the interaction of A beta PP with the gamma-secretase complex. Thus, the present study revealed an essential role for the GxxxG motif in the interaction of A beta PP with the gamma-secretase complex and the formation of A beta.