| GGA3 (Golgi‑localized, γ‑ear‑containing, ADP‑ribosylation‑factor‑binding protein 3) is a monomeric coat‑like adaptor of the GGA family that regulates cargo sorting and trafficking between the trans‑Golgi network and endolysosomal compartments in mammalian cells. The protein contains a VHS domain that recognizes acidic cluster–dileucine (DXXLL) motifs on cargo receptors such as the mannose‑6‑phosphate receptors, a GAT domain that binds activated Arf1‑GTP at the Golgi membrane, a hinge region that recruits clathrin, and a GAE domain that bears structural similarity to the γ‑ear of adaptor protein 1 and engages additional sorting effectors. At the Golgi, Arf1‑dependent recruitment of GGA3 promotes the concentration of mannose‑6‑phosphate receptor–acid hydrolase complexes into clathrin‑coated carriers that transport lysosomal enzymes from the Golgi to endosomes and lysosomes, and loss of GGA function reduces sorting efficiency and increases missorting and secretion of acid hydrolases. GGA3 mediates the trafficking of membrane-associated proteins, such as the β-site amyloid precursor protein–cleaving enzyme (BACE), targeting BACE to lysosomes for degradation and thereby limiting its cell-surface and endosomal levels and activity. During apoptosis and cerebral ischemia, GGA3 is cleaved by caspase‑3 at Asp313, which reduces full‑length GGA3 and impairs BACE lysosomal targeting, leading to BACE accumulation and enhanced amyloid‑β production, a pathway that is mechanistically linked to neurodegenerative conditions such as Alzheimer’s disease. GGA3 also acts as a recycling adaptor for certain receptor tyrosine kinases and can be modulated by interacting partners and post‑translational events. |
Lane 1: Jurkat
