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

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 domain, the dimer containing the ³³Gly-x-x-x-Gly³⁷ motif in the interface promoted the Aβ₄₂ processing line and 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 Aβ_43/40. 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 ²⁵Gly-x-x-x-Gly²⁹ interface. Thus, crossing angles imposed by precise dimeric orientations control γ-secretase initial cleavage at Aβ₄₈ or Aβ_49, linking the former to enhanced signaling and Aβ₄₂ production.