FE65 Recognition Rewires the Dynamic Contact Network of the Amyloid Precursor Protein Intracellular Domain

Abstract

The amyloid precursor protein intracellular domain (AICD) is a short, intrinsically disordered signaling fragment that mediates interactions with adaptor proteins involved in APP trafficking and transcription-associated regulation. Among these partners, FE65 recognizes the conserved YENPTY-containing region of AICD, yet the ensemble-level mechanism underlying this interaction remains unclear. Here, we use molecular dynamics simulations to compare unbound and bound AICD together with YENPTY-motif mutant variants. In the unbound state, AICD samples a heterogeneous conformational ensemble dominated by disordered states while retaining transient local structure and recurrent intramolecular contacts. Upon FE65 binding, AICD does not collapse into a single rigid conformation; instead, its conformational ensemble is redistributed toward interaction-compatible substates. Residue-resolved contact analyses identify localized interaction hotspots within and adjacent to the YENPTY region, including aromatic and polar residues that dominate the bound-state contact network. Mutations within the YENPTY motif alter the balance between compact and extended conformations while preserving the intrinsically disordered character of the peptide. Together, these results support a recognition mechanism in which FE65 binds a partially organized AICD ensemble via localized interaction hotspots and ensemble reweighting, rather than through complete disorder-to-order folding. This work provides a molecular framework for understanding APP intracellular-tail recognition and its regulation by sequence-localized perturbations. More broadly, these findings illustrate how intrinsically disordered motifs can achieve specific molecular recognition through redistribution of dynamic contact networks without undergoing complete disorder-to-order transitions.