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

Amyloid precursor protein (APP) cleavage by the beta 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 gamma-secretase. Of all possible dimeric orientations imposed by a coiled coil to the C99 TM-cytosolic domain, the dimer (cc-del7) containing 33Gly-x-x-x-Gly37 in the interface promoted Abeta 42 processing line and AICD (APP Intracellular Domain)-dependent gene transcription, including BACE1 mRNA induction, enhancing amyloidogenic signaling. Another orientation exhibiting 25Gly-x-x-x-Gly29 in the interface (cc-del6) favored processing to Abeta 43/40, induced significantly less gene transcription, while promoting formation of SDS-resistant 'Abeta-like' oligomers, reminiscent of Abeta peptide oligomers. These required both Val24 of a pro-beta motif and the 25Gly-x-x-x-Gly29 interface. Thus, crossing angles imposed by dimeric orientations give access to gamma-secretase at Abeta 48 or Abeta 49, linking the former to enhanced signaling and Abeta 42. We discuss avenues of blocking amyloidogenic processing.