The membrane protein FeoB contains an intramolecular G protein essential for Fe(II) uptake in bacteria.

G proteins are critical for the regulation of membrane protein function and signal transduction. Nevertheless, coupling between G proteins and membrane proteins with multiple membrane-spanning domains has so far been observed only in higher organisms. Here we show that the polytopic membrane protein FeoB, which is essential for Fe(II) uptake in bacteria, contains a guanine-nucleotide-specific nucleotide binding site. We identify the G4-motif, NXXD, responsible for guanine nucleotide specificity, and show that GTP hydrolysis occurs very slowly. In contrast to typical G proteins, the association and dissociation of GDP were found to be faster than for GTP, suggesting that in the absence of additional factors, FeoB's G protein domain may exist mostly in the GTP-bound form. Furthermore, the binding of GTP is required for efficient Fe(II) uptake through the FeoB-dependent system. Notably, even in bacteria, this covalent linkage between a G protein and a polytopic membrane protein appears, to our knowledge, to be unique. These findings raise the intriguing question whether FeoB represents a primordial archetype of G protein-regulated membrane proteins.