Molecular Basis of RING E3 Ligase Pirh2 and HECT E3 Ligase Itch Interaction.

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Proteins are one of the most important group of molecules in the human body. Regulation of protein stability and turnover is a key task in the cell. The majority of proteins are degraded by the ubiquitin (Ub)-proteasome pathway (UPP). The UPP affects a wide variety of cellular processes and substrates and defects in the UPP can result in the pathogenesis of human diseases. The central role of the UPP in biology has been recognized with the Nobel Prize for Chemistry in 2004. Ubiquitin-mediated protein degradation is a three-step process involving three enzymes: E1 (Ub-activating enzyme), E2 (Ub-conjugating enzyme), and E3 (Ub protein ligase). A new class of ubiquitination enzyme, E4 (a Ub chain assembly factor), was recently shown to be necessary for the degradation of some proteins via the ubiquitin fusion degradation pathway. Together, these enzymes catalyze the covalent attachment of one or more ubiquitin moieties to protein lysine residues. E3 enzymes play a central role in the recognition and ubiquitination of substrates and fall into three subgroups: (i) HECT domain ligases such as E6-APand Itch; (ii) RING domain ligases, including Pirh2 and Mdm2; and (iii) U-box domain ligases representing a non-canonical RING domain such as UFD2 and CHIP (carboxyl terminus of Hsp70-interacting protein). The ubiquitinated proteins are subsequently targeted for degradation by the 26S proteasome.******Our laboratory is studying the regulation and function in the body of two molecules known as Pirh2 and Itch that may be able to regulate cell growth. The two molecules belong to the E3 ligase family, which promote protein degradation. We previously demonstrated that Pirh2 can negatively regulate Itch activities and functions. Our research team will use advanced laboratory tools to explore the body's systems for controlling levels of Itch and how this control relates to cell growth. In particular, we will work towards an understanding of whether the molecules Pirh2 and Itch are critical parts of these control systems and how they can be influenced. Our plan is to study the two molecules in human cells, and to learn their relationship to each other and to other molecules that are involved with cell growth and normal development. Thus, the outcome of this proposal has significant implications for cell biology. We are hopeful that our research will contribute to our understanding of the molecular mechanism of interaction between RING E3 ligase Pirh2 and HECT E3 ligase Itch.