INVESTIGATING THE STRUCTURAL BASIS OF IME2 REGULATION AND SUBSTRATE SPECIFICITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cells that make up an animal or human normally divide a specific number of times before they stop and take on properties that allow them to perform specific functions. One particular cell type ultimately forms sperm in males and egg cells in females; these cells are essential for reproduction. We are using a model system to investigate factors that are essential for growing cells to initiate the program leading to sperm or eggs. A protein referred to as Ime2 (Mak1 in humans) is responsible for promoting the process of sperm and egg formation. Ime2 performs this function by modifying the activity of a specific set of other proteins at just the right time during development. Loss of Ime2 activity leads to infertility, and improper regulation of Ime2 can lead to chromosome damage In humans this damage might result in birth defects such as Downs Syndrome. Additionally, if Ime2 activity is induced in growing cells it can lead to cell death. We are exploring the mechanisms that regulate Ime2 activity by modeling the 3-dimensional structure of the protein to gain insight into how it identifies the proteins that it regulates. Additionally this investigation will lead to new insights regarding how Ime2 activity is regulated. By discovering the details of how this enzyme functions, what other proteins it regulates, and how it accumulates in the right place at the right time, we hope to gain a deeper understanding of human development, and be able to design rational strategies to overcome some types of infertility.