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Elucidating specificity and mechanism of the ubiquitination machinery

Subject Area Biochemistry
Term from 2013 to 2021
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 240707550
 
Final Report Year 2022

Final Report Abstract

Ubiquitination is a central posttranslational modification in eukaryotic cells that regulates the lifetimes, abundance, localization, functions, and interactions of the modified proteins. This requires that ubiquitination, in turn, is specific and tightly controlled. As a consequence, de-regulation of the ubiquitin system is linked to various human diseases, rendering this system a surging arena for therapeutic efforts. Ubiquitination reactions are driven by a cascade of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3) activities, counteracted by deubiquitinases. E3s typically drive substrate recognition and can determine the specificity of modification, together with their cooperating E2. This project focused on dissecting the structural mechanisms of E2s and HECT-type E3s – two diseaserelevant, yet therapeutically unexploited classes of ubiquitination enzymes. Using structural, biochemical, biophysical, and cell biological approaches, we unveiled two structurally and functionally distinct autoinhibition mechanisms in the human E2 UBE2S, a key regulator of the cell cycle. The conformational transitions of UBE2S between its active and inhibited states that we discovered, provide a paradigm for how mutually exclusive intra- and intermolecular interactions modulate the concentrations and activities of E2s, thereby contributing to the precision of ubiquitin signaling. Moreover, we delineated how the HECT-type ligases HUWE1 and E6AP interact with ubiquitin substrates, uncovering critical determinants of specificity, catalysis, regulation, and conformational dynamics of their catalytic domain. We also contributed to the development of a chemical biology-based crosslinking strategy to reconstitute ternary complexes of E2s and HECT-type ligases, respectively, with two ubiquitin substrates. Structural analysis of these complexes will provide keys to understanding specificity in ubiquitin modifications and associated functions. Besides these research accomplishments, the Emmy Noether Programme has allowed me to establish an internationally visible research team, gain expertise as a supervisor and mentor, and secure attractive external offers, leading me to proceed to a position as an Independent Group Leader at the Max Planck Institute for Multidisciplinary Sciences in Göttingen.

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