Parish C A, Brazil D P, Rando R R
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Biochemistry. 1997 Mar 4;36(9):2686-93. doi: 10.1021/bi961844r.
The gamma subunits of heterotrimeric G proteins are isoprenylated/methylated on their carboxy termini. The photoreceptor G protein, transducin, is farnesylated/methylated at this position. Since the isoprenyl group is required for G protein function, it is of great interest to determine the mechanism by which the farnesyl group of Tgamma interacts with the other transducin subunits and/or the activated photoreceptor, rhodopsin. Farnesylcysteine derivatives (N-acetyl-S-farnesyl-L-cysteine and farnesylated peptides) have been previously shown to have effects on transducin activity at high concentrations. Here, an extensive survey is done of farnesylcysteine analogs and other lipid molecules, which are tested for their ability to inhibit GTP/GDP exchange in transducin catalyzed by photolyzed rhodopsin. These studies are carried out to determine the nature of the inhibition process. While it does not appear that these molecules exhibit the specificity which would characterize a ligand-receptor type mechanism, the results suggest that these compounds are not acting in a nonspecific detergent-like manner either. The most likely mode of action of famesylcysteine analogs is that they interfere with the lipid-lipid based association of Talpha and Tbetagamma through the lipid modifications present on each subunit.
异源三聚体G蛋白的γ亚基在其羧基末端进行异戊二烯化/甲基化修饰。光感受器G蛋白转导素在该位置进行法尼基化/甲基化修饰。由于异戊二烯基团是G蛋白功能所必需的，因此确定转导素γ亚基的法尼基基团与其他转导素亚基和/或活化的光感受器视紫红质相互作用的机制具有重要意义。法尼基半胱氨酸衍生物（N-乙酰基-S-法尼基-L-半胱氨酸和法尼基化肽）先前已被证明在高浓度下对转导素活性有影响。在此，对法尼基半胱氨酸类似物和其他脂质分子进行了广泛研究，测试它们抑制视紫红质光解催化的转导素中GTP/GDP交换的能力。进行这些研究以确定抑制过程的性质。虽然这些分子似乎没有表现出配体-受体型机制所特有的特异性，但结果表明这些化合物也不是以非特异性洗涤剂样方式起作用。法尼基半胱氨酸类似物最可能的作用方式是它们通过每个亚基上存在的脂质修饰干扰Tα和Tβγ基于脂质的结合。
