Obiettivo Cellular proteins are prone to misfolding and aggregation, particularly under harsh environmental conditions. To counteract this danger, all organisms from bacteria to humans evolved sophisticated protein quality control networks. The mechanisms employed in them tend to represent some of the most exciting biochemistry occurring in living cells.In Gram-positive bacteria, the key factors combating protein damage include a specialized protein kinase phosphorylating arginine residues (McsB), the central housekeeping protease (ClpP), as well as a AAA chaperone targeting aggregated proteins (ClpC). We find this quality-control system, organized around a distinct protein phospho mark (phosphoarginine, pArg), a fascinating model to investigate novel principles of dealing with proteotoxic stress.Using an integrative approach, we will delineate the precise role of protein arginine phosphorylation in the bacterial stress response. We will first analyze how this unique modification influences the stability and function of targeted proteins in vitro and in vivo. We are particularly interested in the possibility of pArg serving as a bacterial, ubiquitin-like degradation signal. We will then address the mechanism and regulation of the protein arginine kinase McsB. This analysis will uncover the specificity of the pArg tagging system. Additionally, these studies will reveal enzymatic innovations connected with the pArg chemistry that, due to the dependence of bacterial virulence on McsB, are of pharmaceutical interest. To address the further processing of pArg-modified proteins, we will perform an in-depth structural characterization of ClpC and related AAA disaggregases. A better understanding of the mechanism and regulation of these HSP100 molecular machines is also highly relevant to uncover general principles of how cells deal with toxic protein aggregates and, in parallel, keep control over their potentially dangerous shredding devices. Campo scientifico natural sciencesbiological sciencesmicrobiologybacteriologymedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibioticsnatural scienceschemical sciencesorganic chemistryaminesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Parole chiave pArg_deg_signal Programma(i) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Argomento(i) ERC-ADG-2015 - ERC Advanced Grant Invito a presentare proposte ERC-2015-AdG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-ADG - Advanced Grant Istituzione ospitante FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH Contribution nette de l'UE € 2 499 299,00 Indirizzo CAMPUS-VIENNA-BIOCENTER 1 1030 Wien Austria Mostra sulla mappa Regione Ostösterreich Wien Wien Tipo di attività Private for-profit entities (excluding Higher or Secondary Education Establishments) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 2 499 299,00 Beneficiari (1) Classifica in ordine alfabetico Classifica per Contributo netto dell'UE Espandi tutto Riduci tutto FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH Austria Contribution nette de l'UE € 2 499 299,00 Indirizzo CAMPUS-VIENNA-BIOCENTER 1 1030 Wien Mostra sulla mappa Regione Ostösterreich Wien Wien Tipo di attività Private for-profit entities (excluding Higher or Secondary Education Establishments) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 2 499 299,00