Objetivo 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. Ámbito científico natural sciencesbiological sciencesmicrobiologybacteriologymedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibioticsnatural scienceschemical sciencesorganic chemistryaminesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Palabras clave pArg_deg_signal Programa(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Tema(s) ERC-ADG-2015 - ERC Advanced Grant Convocatoria de propuestas ERC-2015-AdG Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-ADG - Advanced Grant Institución de acogida FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH Aportación neta de la UEn € 2 499 299,00 Dirección CAMPUS-VIENNA-BIOCENTER 1 1030 Wien Austria Ver en el mapa Región Ostösterreich Wien Wien Tipo de actividad Private for-profit entities (excluding Higher or Secondary Education Establishments) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 2 499 299,00 Beneficiarios (1) Ordenar alfabéticamente Ordenar por aportación neta de la UE Ampliar todo Contraer todo FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH Austria Aportación neta de la UEn € 2 499 299,00 Dirección CAMPUS-VIENNA-BIOCENTER 1 1030 Wien Ver en el mapa Región Ostösterreich Wien Wien Tipo de actividad Private for-profit entities (excluding Higher or Secondary Education Establishments) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 2 499 299,00
