摘要：SummaryAmyloid 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 the33Gly-x-x-x-Gly37motif in the interface promoted the Aβ42processing line and APP intracellular domain-dependent gene transcription, including the induction of BACE1 mRNA, enhancing amyloidogenic processing and signaling. Another orientation exhibiting the25Gly-x-x-x-Gly29motif 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 the25Gly-x-x-x-Gly29interface. Thus, crossing angles imposed by precise dimeric orientations control γ-secretase initial cleavage at Aβ48or Aβ49,linking the former to enhanced signaling and Aβ42production.Graphical AbstractDisplay OmittedHighlights•C99 dimeric transmembrane orientations regulate γ-secretase processing line•Aβ42production and signaling are linked to the33Gly-x-x-x-Gly37interface•SDS-resistant oligomers require the25Gly-x-x-x-Gly29interface and a pro-β motif•C99 dimeric orientations impact its localization and processing by PSEN1 or PSEN2Biological Sciences; Biochemistry; Molecular Biology; Neuroscience
