The GGAs strike again: Cargo capture!

Mannose 6-phosphate receptors are essential for the targeting of soluble lysosomal hydrolases from the trans-Golgi network (TGN) to lysosomes in all mammalian cells. This pathway is mediated by clathrin-coated vesicles (CCVs) that bud from the TGN and selectively concentrate these receptor–ligand complexes. Assembly of CCVs on Golgi membranes is initiated by the binding of the GTP-bound, active form of the small GTPase ARF, which generates high-affinity membrane-binding sites for the heterotetrameric AP-1 adaptor complex, and this in turn recruits clathrin triskelia to form the coat. While the vesicle budding step seems reasonably well understood, the cargo inclusion step and the components of the cargo sorting machinery in this transport step are less well characterized. Both the AP-1 adaptor complex and GGAs (‘Golgi-associated, γ-adaptin homologous, ARF-interacting proteins’) are implicated in this function. The GGAs constitute a conserved multidomain protein family implicated in traffic between the Golgi complex and endosomes. Mammalian and yeast GGAs have a modular structure, consisting of a VHS, GAT, hinge and γ-adaptin ear domain. It has recently been shown that the GAT domain binds directly to GTP-bound ARF and can target a GFP-reporter protein to Golgi membranes and stabilize ARF1–GTP on Golgi membranes in vivo, most likely by slowing GTP hydrolysis on ARF through interference with the action of GTPase-activating proteins (GAPs). The hinge and ear domain on the GGAs interact with clathrin (see p. 239 of the June TCB issue for further references). However, the function of the VHS domain on GGAs had until now remained elusive.