Structure and Function of ICMT Methyltransferase

描述（由申请人提供）：翻译后修饰CaaX基序提供了一种调节包括Ras在内的细胞信号蛋白的方法。CaaX基序的加工涉及三种顺序作用的酶：蛋白质丙烯基转移酶、丙烯基-CaaX蛋白酶和异丙烯半胱氨酸羧基甲基转移酶（ICMT）。药物抑制戊烯基转移酶已被证明是一种有效的抗癌治疗方法。ICMT的生化抑制可以抵抗Ras依赖性的致癌转化。目前缺乏ICMT的药理学抑制剂，但将为治疗发展提供一条途径。本研究拟研究ICMT的结构和功能，以更好地了解其酶促机制、结构，并制定抑制策略。这一过程将包括ICMT的纯化和溶解，伴随着酶分析以确保活性和确定ICMT的作用机制。此外，人类ICMT的结构将被确定用于辅助酶抑制剂的设计和进一步了解蛋白质的ICMT甲基化的分子机制。这些数据将提供ICMT的生化和结构特性的详细描述，重点是抑制作用。

DESCRIPTION (provided by applicant): Post-translational modification of CaaX motifs provides a means to regulate cell signaling proteins, including Ras. The processing of CaaX motifs involves three sequentially acting enzymes: protein prenyltransferases, prenyI-CaaX proteases, and isoprenylcysteine carboxyl methyltransferase (ICMT). Pharmacologic inhibition of prenyltransferase has shown utility as an anti-cancer therapy. Biochemical inhibition of ICMT confers resistance to Ras dependent oncogenic transformation. Pharmacologic inhibitors of ICMT are lacking but would provide an avenue for therapeutic development. This study proposes to study the structure and function of ICMT to better understand its enzymatic mechanism, structure, and to develop inhibition strategies. This process will include purification and solublization of ICMT, accompanied by enzymatic analysis to insure activity and determine the mechanism of action for ICMT. Additionally the structure of human ICMT will be determined for use in aiding enzyme inhibitor design and further understanding of the molecular mechanism of ICMT methylation of proteins. This data will provide a detailed description of the biochemical and structural properties of ICMT, with a focus on inhibition.