Structure and Function of ICMT Methyltransferase

Duke University, Durham NC

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Abstract

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.