The structural GDP/GTP cycle of human Arf6

The small GTP-binding protein Arf6 coordinates membrane traffic at the plas ma membrane with aspects of cytoskeleton organization. This function does n ot overlap with that of other members of the ADP-ribosylation factor (Arf) family, although their switch regions, which are their major sites of inter action with regulators and effecters, have virtually identical sequences. H ere we report the crystal structure of full-length, non-myristoylated human Arf6 bound to GTP gammaS. Unlike their GDP-bound forms, the active forms o f Arf6 and Arf1 are very similar. Thus, the switch regions are discriminato ry elements between Arf isoforms in their inactive but not in their active forms, a property that may generalize to other families of small G proteins . This suggests that GTP-bound Arfs may establish specific interactions out side the switch regions and/or be recognized in their cellular context rath er than as isolated proteins. The structure also allows further insight int o the lack of spontaneous GTPase activity of Arf proteins.