Casey P J, Solski P A, Der C J, Buss J E
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75235.
Proc Natl Acad Sci U S A. 1989 Nov;86(21):8323-7. doi: 10.1073/pnas.86.21.8323.
Association of oncogenic ras proteins with cellular membranes appears to be a crucial step in transformation, ras is synthesized as a cytosolic precursor, which is processed to a mature form that localizes to the plasma membrane. This processing involves, in part, a conserved sequence, Cys-Ali-Ali-Xaa (in which Ali is an amino acid with an aliphatic side chain and Xaa is any amino acid), at the COOH terminus of ras proteins. Yeast a-factor mating hormone precursor also possesses a COOH-terminal Cys-Ali-Ali-Xaa sequence. However, while the COOH-terminal cysteine has been implicated as a site of palmitoylation of ras proteins, in mature a-type mating factor this residue is modified by an isoprenoid, a farnesyl moiety. We asked whether the Cys-Ali-Ali-Xaa sequence signaled different modifications for the yeast peptides (farnesylation) than for ras proteins (palmitoylation) or whether ras proteins were similar to the mating factors and contained a previously undiscovered isoprenoid. We report here that the processing of ras proteins involves addition of a farnesyl moiety, apparently at the COOH-terminal cysteine analogous to the cysteine modified in the yeast peptides, and that farnesylation may be important for membrane association and transforming activity of ras proteins.
致癌性Ras蛋白与细胞膜的结合似乎是细胞转化过程中的关键步骤。Ras蛋白最初作为胞质前体被合成，随后被加工成定位于质膜的成熟形式。这种加工过程部分涉及Ras蛋白COOH末端的一个保守序列，即Cys-Ali-Ali-Xaa（其中Ali是带有脂肪族侧链的氨基酸，Xaa是任意氨基酸）。酵母α-因子交配激素前体也具有COOH末端的Cys-Ali-Ali-Xaa序列。然而，虽然COOH末端的半胱氨酸被认为是Ras蛋白棕榈酰化的位点，但在成熟的α型交配因子中，该残基被类异戊二烯（法尼基部分）修饰。我们研究了Cys-Ali-Ali-Xaa序列对酵母肽（法尼基化）和Ras蛋白（棕榈酰化）的修饰信号是否不同，或者Ras蛋白是否与交配因子类似并含有一种此前未被发现的类异戊二烯。我们在此报告，Ras蛋白的加工过程涉及添加一个法尼基部分，显然是在COOH末端的半胱氨酸处，类似于酵母肽中被修饰的半胱氨酸，并且法尼基化可能对Ras蛋白的膜结合和转化活性很重要。
