Phosducin induces a structural change in transducin βγ

Background: Phosducin binds tightly to the beta gamma subunits (G(t)beta gamma) of the heterotrimeric G protein transducin, preventing G(t)beta gamma reassociation with G(t)alpha-GDP and thereby inhibiting the G-protein cycle. Phosducin-like proteins appear to be widely distributed and may play important roles in regulating many heterotrimeric G-protein signaling pathways. Results: The 2.8 Angstrom crystal structure of a complex of bovine retinal phosducin with G(t)beta gamma shows how the two domains of phosducin cover one side and the top of the seven-bladed beta propeller of G(t)beta gamma. The binding of phosducin induces a distinct structural change in the beta propeller of G(t)beta gamma, such that a small cavity opens up between blades 6 and 7. Electron density in this cavity has been assigned to the farnesyl moiety of the gamma subunit. Conclusions: beta gamma subunits of heterotrimeric G proteins can exist in two distinct conformations. In the R (relaxed) state, corresponding to the structure of the free beta gamma or the structure of beta gamma in the alpha beta gamma heterotrimer, the hydrophobic farnesyl moiety of the gamma subunit is exposed, thereby mediating membrane association, in the T (tense) state, as observed in the phosducin-G(t)beta gamma structure, the farnesyl moiety of the gamma subunit is effectively buried in the cavity formed between blades 6 and 7 of the beta subunit. Binding of phosducin to G(t)beta gamma induces the formation of this cavity, resulting in a switch from the R to the T conformation. This sequesters py from the membrane to the cytosol and turns off the signal-transduction cascade. Regulation of this membrane association/dissociation switch of G(t)beta gamma by phosducin may be a general mechanism for attenuation of G protein coupled signal transduction cascades.