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-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 25Gly-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 25Gly-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.
C99 dimeric transmembrane orientations regulate γ-secretase processing line
Aβ 42 production and signaling are linked to the 33Gly-x-x-x-Gly 37 interface
SDS-resistant oligomers require the 25Gly-x-x-x-Gly 29 interface and a pro-β motif
C99 dimeric orientations impact its localization and processing by PSEN1 or PSEN2
Biological Sciences; Biochemistry; Molecular Biology; Neuroscience