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 AICD (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 Aβ_43/40. It induced significantly less gene transcription, while promoting formation of SDS-resistant “Aβ-like” oligomers, reminiscent of Aß peptide oligomers. These required both Val24 of a pro-ß 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 Aβ_49, linking the former to enhanced signaling and Aβ₄₂ production.

β-分泌酶切割淀粉样前体蛋白（APP）会产生C99跨膜（TM）蛋白，该蛋白包含三个诱导二聚化的Gly-xxx-Gly基序。我们证明，二聚体C99 TM方向通过γ-分泌酶调节精确的切割线。在卷曲螺旋作用于C99 TM域的所有可能的二聚体取向中，界面中包含³³ Gly-xxx-Gly ³⁷基序的二聚体促进了_Aβ42加工线和AICD（APP细胞内域）依赖性基因转录，包括BACE1 mRNA的诱导，增强淀粉样蛋白的加工和信号传导。在界面上显示²⁵ Gly-xxx-Gly ²⁹基序的另一种取向有利于加工成Aβ_43/40。它诱导的基因转录明显减少，同时促进了抗SDS的“Aβ样”寡聚体的形成，让人联想到Aß肽寡聚体。这些都需要pro-β基序的Val24和²⁵ Gly-xxx-Gly ²⁹界面。因此，交叉角由精确二聚体取向强加在Aβ控制γ分泌初始裂解₄₈或Aβ _49，连接前者到增强的信令和Aβ ₄₂的产生。