Loew A, Ho Y K, Blundell T, Bax B
Department of Biochemistry and Molecular Biology, University of Illinois at Chicago, IL 60612-7334, USA.
Structure. 1998 Aug 15;6(8):1007-19. doi: 10.1016/s0969-2126(98)00102-6.
Phosducin binds tightly to the beta gamma subunits (Gt beta gamma) of the heterotrimeric G protein transducin, preventing Gt beta gamma reassociation with Gt 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.
The 2.8 A crystal structure of a complex of bovine retinal phosducin with Gt beta gamma shows how the two domains of phosducin cover one side and the top of the seven-bladed beta propeller of Gt beta gamma. The binding of phosducin induces a distinct structural change in the beta propeller of Gt 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.
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-Gt 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 Gt beta gamma induces the formation of this cavity, resulting in a switch from the R to the T conformation. This sequesters beta gamma from the membrane to the cytosol and turns off the signal-transduction cascade. Regulation of this membrane association/dissociation switch of Gt beta gamma by phosducin may be a general mechanism for attenuation of G protein coupled signal transduction cascades.
磷光蛋白紧密结合于异源三聚体G蛋白转导素的βγ亚基（Gtβγ），阻止Gtβγ与Gtα - GDP重新结合，从而抑制G蛋白循环。类磷光蛋白似乎广泛分布，可能在调节许多异源三聚体G蛋白信号通路中发挥重要作用。
牛视网膜磷光蛋白与Gtβγ复合物的2.8埃晶体结构显示了磷光蛋白的两个结构域如何覆盖Gtβγ七叶β螺旋桨的一侧和顶部。磷光蛋白的结合在Gtβγ的β螺旋桨中诱导了明显的结构变化，使得在叶片6和7之间形成了一个小腔。该腔内的电子密度已被确定为γ亚基的法尼基部分。
异源三聚体G蛋白的βγ亚基可以以两种不同的构象存在。在R（松弛）状态下，对应于游离βγ的结构或αβγ异源三聚体中βγ的结构，γ亚基的疏水法尼基部分暴露，从而介导膜结合。在T（紧张）状态下，如在磷光蛋白 - Gtβγ结构中观察到的，γ亚基的法尼基部分有效地埋在β亚基叶片6和7之间形成的腔内。磷光蛋白与Gtβγ的结合诱导了这个腔的形成，导致从R构象向T构象的转变。这将βγ从膜隔离到细胞质中，并关闭信号转导级联反应。磷光蛋白对Gtβγ这种膜结合/解离开关的调节可能是减弱G蛋白偶联信号转导级联反应的一般机制。
