James G, Olson E N
Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Houston 77030.
Biochemistry. 1990 Mar 20;29(11):2623-34. doi: 10.1021/bi00463a001.
From the studies presented above, it is obvious that fatty acylation is a common modification among proteins involved in cellular regulatory pathways, and in certain cases mutational analyses have demonstrated the importance of covalent fatty acids in the functioning of these proteins. Indeed, certain properties provided by fatty acylation make it an attractive modification for regulatory proteins that might interact with many different substrates, particularly those found at or near the plasma membrane/cytosol interface. In the case of intracellular fatty acylated proteins, the fatty acyl moiety allows tight binding to the plasma membrane without the need for cotranslational insertion through the bilayer. For example, consider the tight, salt-resistant interaction of myristoylated SRC with the membrane, whereas its nonmyristoylated counterpart is completely soluble. Likewise for the RAS proteins, which associate weakly with the membrane in the absence of fatty acylation, while palmitoylation increases their affinity for the plasma membrane and their biological activity. Fatty acylation also permits reversible membrane association in some cases, particularly for several myristoylated proteins, thus conferring plasticity on their interactions with various signaling pathway components. Finally, although this has not been demonstrated, it is conceivable that covalent fatty acid may allow for rapid mobility of proteins within the membrane. Several questions remain to be answered concerning requirements for fatty acylation by regulatory proteins. The identity of the putative SRC "receptor" will provide important clues as to the pathways in which normal SRC functions, as well as into the process of transformation by oncogenic tyrosine kinases. The possibility that other fatty acylated proteins associate with the plasma membrane in an analogous manner also needs to be investigated. An intriguing observation that can be made from the information presented here is that at least three different families of proteins involved in growth factor signaling pathways encode both acylated and nonacylated members, suggesting that selective fatty acylation may provide a means of determining the specificity of their interactions with other regulatory molecules. Further studies of fatty acylated proteins should yield important information concerning the regulation of intracellular signaling pathways utilized during growth and differentiation.
从上述研究可以明显看出，脂肪酰化是参与细胞调节途径的蛋白质中常见的一种修饰，在某些情况下，突变分析已证明共价脂肪酸对这些蛋白质功能的重要性。事实上，脂肪酰化赋予的某些特性使其成为调节蛋白颇具吸引力的一种修饰，这些调节蛋白可能与许多不同的底物相互作用，尤其是那些位于质膜/胞质溶胶界面或其附近的底物。对于细胞内脂肪酰化的蛋白质而言，脂肪酰部分使其能够紧密结合到质膜上，而无需通过双层膜进行共翻译插入。例如，考虑肉豆蔻酰化的SRC与膜的紧密、耐盐相互作用，而其未肉豆蔻酰化的对应物则完全可溶。RAS蛋白也是如此，在没有脂肪酰化的情况下，它们与膜的结合较弱，而棕榈酰化则增加了它们对质膜的亲和力及其生物学活性。脂肪酰化在某些情况下还允许可逆的膜结合，特别是对于几种肉豆蔻酰化的蛋白质，从而赋予它们与各种信号通路成分相互作用的可塑性。最后，尽管尚未得到证实，但可以想象共价脂肪酸可能使蛋白质在膜内快速移动。关于调节蛋白进行脂肪酰化的要求，仍有几个问题有待解答。假定的SRC“受体”的身份将为正常SRC发挥功能的途径以及致癌酪氨酸激酶的转化过程提供重要线索。其他脂肪酰化蛋白质以类似方式与质膜结合的可能性也需要进行研究。从这里给出的信息可以得出一个有趣的观察结果，即参与生长因子信号通路的至少三个不同蛋白质家族都编码酰化和未酰化成员，这表明选择性脂肪酰化可能提供一种确定它们与其他调节分子相互作用特异性的方法。对脂肪酰化蛋白质的进一步研究应该会产生有关生长和分化过程中利用的细胞内信号通路调节的重要信息。
