Dimeric Transmembrane Orientations of APP/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 domain, the dimer containing the ³³ Gly-x-x-x-Gly ³⁷ motif in the interface promoted the Aβ ₄₂ processing line and APP intracellular domain-dependent gene transcription, including the induction of BACE1 mRNA, enhancing amyloidogenic processing and signaling. Another orientation exhibiting the ²⁵ Gly-x-x-x-Gly ²⁹ 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 ²⁵ Gly-x-x-x-Gly ²⁹ interface. Thus, crossing angles imposed by precise dimeric orientations control γ-secretase initial cleavage at Aβ ₄₈ or Aβ _49, linking the former to enhanced signaling and Aβ ₄₂ production.
Competing Interests: S.N.C. is co-founder of Alsatech – Boston, MA and close family is owning stock in A.C. Immune Lausanne. The work of this manuscript is not linked to any current project at Alsatech or A.C. Immune, which are companies that work in the field of Alzheimer's disease.
(© 2020 The Author(s).)