Objectif To understand how molecular machines execute their function, a multidisciplinary approach combining structural biology with biochemical and computational studies is required. In this project, I will couple these three methodologies to understand the dynamic interactions and regulatory mechanisms of the 26S proteasome by cryo-EM single particle analysis.Recent work from our lab and others resulted in a pseudo-atomic structure of the 26S proteasome. At the same time, cryo-EM technology has been revolutionized by automated data acquisition schemes and new electron detectors, which empower us to explore dynamic structures at high resolution. Thus, now we can not only “watch” conformational changes in macromolecules as they perform their function, but also structurally analyze their transient interactions. In the case of the 26S proteasome, binding of both proteasome interacting proteins (PIPs) and ubiquitylated substrates is crucial for proteasome assembly and function, but how these interactions occur remains poorly understood.The major goals of this proposal will be to 1) understand the functional and structural interactions of the proteasome and various PIPs, and 2) how the proteasome recognizes different ubiquitylated substrates through different ubiquitin receptors. These results will contribute not only to the general understanding of proteasome regulation, but also to deciphering the code of ubiquitin signaling employed in various cellular pathways, thus impacting different areas of biochemistry, molecular biology and cell biology. Furthermore, this will be the first systematic exploration of a structural “interactome”, which may pave the way for further studies on other macromolecules. Finally, given the role of the proteasome in numerous human diseases, a detailed knowledge of the molecular mechanisms for its regulation can also have significant biomedical relevance and may lead the development of novel, more specific drugs targeting the 26S proteasome. Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencescell biologynatural sciencesbiological sciencesmolecular biologystructural biology Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2013-CIG - Marie-Curie Action: "Career Integration Grants" Appel à propositions FP7-PEOPLE-2013-CIG Voir d’autres projets de cet appel Régime de financement MC-CIG - Support for training and career development of researcher (CIG) Coordinateur MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Contribution de l’UE € 75 000,00 Adresse HOFGARTENSTRASSE 8 80539 Munchen Allemagne Voir sur la carte Région Bayern Oberbayern München, Kreisfreie Stadt Type d’activité Research Organisations Contact administratif Anne Katrin Werenskiold (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
