Structural and functional analysis of APP695

Abstract

APP695 is a neuronal isoform of the amyloid precursor protein, involved in synaptic functions. Post-translational modifications like phosphorylation and ubiquitination play critical roles in regulating APP695 levels and trafficking, which affects its cleavage. Moreover, dysfunction in APP cleavage can lead to the accumulation of neurotoxic fragments associated with Alzheimer's disease. This study used in silico tools including ΔG Predictor, TOPCONS, NetPhos 3.1, and GPS-Uber to perform structural and functional analysis of APP695. Several potential phosphorylation sites were identified. Among them, residues T653, T655, Y682, T686 and Y687 belong to the sorting motifs in the C-terminal region, while T668 is located between them, along with a key ubiquitination site K688 which plays a critical role in trafficking and processing of APP695. Notably, phosphorylation at T668 increases the interaction with β-secretase cleavage and disrupt adaptor protein interactions, shifting APP processing toward amyloidogenic pathways. These findings suggest that the interplay between phosphorylation and ubiquitination could contribute to Aβ production and AD progression. These findings offer insights into how post-translational modifications may regulate APP behavior and contribute to AD pathology.