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

Summary: 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 dimer...

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Main Authors: Florian Perrin, Nicolas Papadopoulos, Nuria Suelves, Rémi Opsomer, Devkee M. Vadukul, Céline Vrancx, Steven O. Smith, Didier Vertommen, Pascal Kienlen-Campard, Stefan N. Constantinescu
Format: Article
Language:English
Published: Elsevier 2020-12-01
Series:iScience
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Online Access:http://www.sciencedirect.com/science/article/pii/S2589004220310841
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Summary:Summary: 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 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 the 25Gly-x-x-x-Gly29 interface. Thus, crossing angles imposed by precise dimeric orientations control γ-secretase initial cleavage at Aβ48 or Aβ49, linking the former to enhanced signaling and Aβ42 production.
ISSN:2589-0042