Helix-Switch Enables C99 Dimer Transition between the Multiple Conformations

C99 is the immediate precursor of amyloid-β (Aβ) and therefore is a central intermediate in the pathway that is believed to result in Alzheimer's disease (AD). Recent studies have shown that C99 dimerization changes the Aβ ratio, but the mechanism remains unclear. Previous studies of the C99 dimer have produced controversial structure models. To address these questions, we investigated C99 dimerization using molecular dynamics (MD) simulations. A helix-switch model was revealed in the formation and transition of the C99 dimer, and six types of conformations were identified. The different conformations show differential exposures of γ-cleavage sites and insertion depths in the bilayer, which may modulate γ-cleavage of C99 and lead to different Aβ levels. Our results redefine C99 dimerization, provide a framework to mediate the current controversial results, and give insights into the understanding of the relationship between C99 dimerization and Aβ formation.