Dimeric Transmembrane Orientations of AAPP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization

Amyloid precursor protein (APP) cleavage by the β secretase produces the C99 transmembrane (TM) protein, which contains three dimerization-inducing Gly-x-x-x-Gly motifs. We demonstrate that dimeric C99 TM orientations regulate the precise cleavage lines by γ-secretase. Of all possible dimeric orientations imposed by a coiled coil to the C99 TM-cytosolic domain, the dimer containing the 33Gly-x-x-x-Gly37 motif in the interface promoted the Aβ42 processing line and AICD (APP Intracellular Domain)-dependent gene transcription, including the induction of BACE1 mRNA, enhancing amyloidogenic processing and signaling. Another orientation exhibiting the 25Gly-x-x-x-Gly29 motif in the interface favored processing to Aβ43/40. It induced significantly less gene transcription, while promoting formation of SDS-resistant “Aβ-like” oligomers, reminiscent of Aβ peptide oligomers. These required both Val24 of a pro-β motif and the interface between 25Gly-x-x-x-Gly29 motifs. Thus, crossing angles imposed by precise dimeric orientations give access to γ-secretase for initial cleavage at Aβ48 or Aβ49, linking the former to enhanced signaling and Aβ42 production. This illustrates that the orientation of APP transmembrane dimers controls the γ-secretases processing lines that switches either towards intracellular signaling or formation of Aβ assemblies. We further discuss avenues of blocking amyloidogenic processing in this regard.