Protein aggregation interfaces of Amyloid-beta 42, Microtubule-associated protein tau, Trafficking protein particle complex subunit 6A delta, and SH3 domain-containing GRB2-like protein B2 (Aβ42/Tau/TRAPPC6AΔ/SH3GLB2 interfaces)

This target refers to the structural interfaces involved in the pathological aggregation of a specific network of proteins associated with Alzheimer's disease, including Amyloid-beta 42 (Aβ42), Microtubule-associated protein tau (Tau), the TRAPPC6AΔ variant, and SH3GLB2 (Endophilin-B2). These proteins are characterized by serine-rich (S-rich) domains that facilitate misfolding and the assembly of neurotoxic aggregates (Kim et al., 2016). TRAPPC6AΔ, a truncated isoform of the TRAPPC6A protein, acts as a nucleating factor that promotes the co-aggregation of Aβ and Tau, while SH3GLB2 is involved in the disruption of autophagic and endocytic pathways linked to these aggregates (Kim et al., 2020). Targeting these interfaces is a therapeutic strategy aimed at preventing the transition from soluble monomers to toxic oligomeric and fibrillar species. Current drug development focuses on monoclonal antibodies and small molecules that bind these interfaces to stabilize native conformations or facilitate the clearance of pathological assemblies from the brain. By disrupting these specific protein-protein interaction sites, researchers hope to halt the progression of neurodegeneration and preserve cognitive function in patients (Selkoe & Hardy, 2016).

Other names

S-rich aggregation-prone proteinsAlzheimer's disease protein aggregate interfacesTRAPPC6A delta-associated aggregatesSerine-rich protein aggregation network

Inhibition of protein-protein interactions at aggregation-prone interfaces to prevent the formation of toxic oligomers and insoluble fibrils, and promotion of aggregate clearance via microglial phagocytosis.