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Periodic Report Summary 1 - TRIM (Structure-Function Studies of the TRIM Family of Ubiquitin E3 Ligases)

The ubiquitin system plays a role in a wide range of cellular processes including protein degradation, cell signaling, transcription regulation and DNA damage response. The regulation of numerous cellular processes by ubiquitin is ascribed to its ability to form a large spectrum of modifications, from monoubiquitination of a target protein to the production of poly-ubiquitin chains with varying linkages and length. Improper regulation of ubiquitination has been observed in many human diseases including cancer, Alzheimer’s, Parkinson’s disease and viral infections. Consequently, understanding the molecular mechanisms of ubiquitination, and specifically the enzymes responsible for ubiquitination is of great interest not only for basic research but also for exploiting these enzymes’ potential as targets for drug design. In the cell more than 900 enzymes are involved in the deposition or removal of ubiquitin and only little is known about their specificity, activity and interaction network. In this work we focus on a group of enzymes known as TRIM proteins that are involved in ubiquitin assembly. This family of proteins plays pivotal roles in many physiological and pathophysiological processes such as immune signaling, transcriptional regulation, apoptosis, cancer and developmental and genetic diseases. Despite the numerous vital roles that TRIM proteins play in the cell, important aspects of their mechanism remain unknown mainly due to their multi-domain architecture, their ability to self-associate into dimers and higher order complexes, and their ability to function not only with ubiquitin but also with ubiquitin-like proteins. In this work, we propose to investigate the molecular mechanism of TRIM25 E3 ligase activity and how they crosstalk with other enzymes involved in ubiquitin pathways. Specifically, we will study how TRIM proteins interact and function with enzymes possessing E2 activity and with target proteins that undergo ubiquitination via this family. To that end we perform a multidisciplinary research involves structural biology via X-ray crystallography, biophysical and biochemical assays, cell biology and bioinformatics. This combination of tools enables us to perform comprehensive research on this protein family that not only will provide mechanistic insight but also will address the suitability of this family as a target for drug design.
My research interest is on the mechanisms of protein modification by ubiquitin and ubiquitin like proteins. The TRIM project is perfectly combined with the efforts of my lab to better understand how ubiquitination is regulated in the cell. I have also generated a productive crosstalk between this project and the other projects in the lab that is on the removal of ubiquitin. In parallel, our finding in that project enabled me to established new collaborations and to promote my professional carrier.

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Life Sciences
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