New Insights into the Structural Rearrangement and Aggregation Properties of Aβ-PrP Cross-Seeding Modulated by Histidine Behaviors

Abstract

Histidine behavior plays a pivotal role in protein folding and misfolding; yet, its influence on cross-seeding during the nucleation phase remains poorly understood. The current study investigates the role of histidine behavior on the structural and aggregation properties during the cross-seeding of Aβ(1–40) and PrP(106–126) peptides. Our findings reveal that all systems tend to form dimeric structures. Antiparallel β-sheet structures predominate in both Aβ and PrP chains across all systems, particularly in the Aβ regions L17-E22, K28–I31, and G33-V39 (except (εεεδ)) and the PrP regions T43-H47 and A52-L61. We found that Aβ and PrP mutually promote structural rearrangement during cross-seeding, forming stable dimers. H-bond analysis confirmed that H6, H13, H14, and H47 are directly involved in H-bond networks, confirming that the histidine behavior plays a critical role in modulating these processes. Our further analysis shows that all systems exhibit characteristic four/five β-strand structures, forming regularly arranged β-strands among the N-termini, CHC, and C-terminus in Aβ, as well as T43-H47 and A52-L61 in PrP. Furthermore, two stacking modes were discussed in our studies. These findings provide mechanistic insights into histidine’s role in amyloid aggregation and highlight the significance of Aβ-PrP cross-seeding interactions in amyloidogenesis, offering potential therapeutic targets for protein misfolding diseases.