Dimeric Transmembrane Orientations Of App/C99 Regulate Gamma-Secretase Processing Line Impacting Signaling And Oligomerization

Amyloid precursor protein (APP) cleavage by the beta-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 gamma-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 A beta(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 A beta(43/40). It induced significantly less gene transcription, while promoting formation of SDS-resistant "Ab-like'' oligomers, reminiscent of Ab peptide oligomers. These required both Val24 of a pro-beta motif and the (25)Gly-x-x-x-Gly(29) interface. Thus, crossing angles imposed by precise dimeric orientations control gamma-secretase initial cleavage at A beta(48) or A beta(49), linking the former to enhanced signaling and A beta(42) production.