ADP-ribosylation factor-binding protein GGA3

GGA3 (ADP-ribosylation factor-binding protein GGA3) is a vesicular trafficking adaptor protein that mediates protein sorting and transport between the trans-Golgi network and endosomes (UniProt: Q9NZ52). It recruits clathrin in an ARF-dependent manner and binds ubiquitinated cargo molecules bearing acidic cluster-dileucine motifs. GGA3 plays a particularly important role in regulating BACE1 (β-secretase) transport, sorting, and protein levels through both VHS domain interactions and ubiquitin recognition.

GGA3 is involved in multiple trafficking pathways including retrograde endosomal transport and recycling of surface receptors such as ADRA2B and NTRK1. Its function in BACE1 trafficking connects it to amyloid precursor protein processing, a central pathway in neurodegeneration.

GGA3 is downregulated in Alzheimer's disease brain tissue (Chaparral AD proteomics). The mean log₂ fold-change was −0.96 compared to age-matched controls in post-mortem brain fractions, indicating reduced protein abundance in AD pathology. This downregulation may impair BACE1 trafficking and sorting, with potential consequences for amyloid-beta generation and clearance in AD neurodegeneration.