Descrizione del progetto DEENESFRITPL Attacco mediato da chaperon agli aggregati proteici Il ripiegamento delle proteine è fondamentale per il loro corretto funzionamento ed è assistito da altre proteine, note come chaperon molecolari. I dati emergenti suggeriscono che i chaperon rompono anche gli aggregati proteici osservati durante la neurodegenerazione nelle malattie di Alzheimer, Parkinson e Huntington. Tuttavia, non è ancora chiaro come questi chaperon eseguano tale funzione di disaggregazione. Il progetto NMR-DisAgg, finanziato dall’UE, intende studiare i meccanismi delle interazioni tra chaperon, superando le sfide associate alla natura dinamica e di breve durata di questi incontri. La delineazione della reazione di disaggregazione offrirà una migliore visione del processo di degenerazione e potenzialmente identificherà nuovi bersagli terapeutici. Mostra l’obiettivo del progetto Nascondi l’obiettivo del progetto Obiettivo Molecular chaperones are a diverse group of proteins critical to maintaining cellular homeostasis. Aside from protein refolding, it has recently been discovered that certain combinations of human chaperones can break apart toxic protein aggregates and even amyloids that have been linked to a host of neurodegenerative diseases. The first chaperones in this disaggregation reaction that are responsible for recognizing and performing initial remodeling of aggregates, are members of the Hsp40 (DnaJ) and small heat shock protein (sHSP) families. Very little, though, is known regarding how these chaperones perform their functions, and characterization of sHsp- and DnaJ-substrate complexes by most structural techniques has proven extremely challenging, as most chaperones are dynamic in nature and typically operate through a series of transient interactions with both their clients and other chaperones.The advanced NMR techniques used in our lab, however, are ideally suited for the study of these exact types of dynamic systems, and include recently developed experiments (CEST, CPMG) that allow us to monitor the transient and low populated protein states typical of chaperone-chaperone and chaperone-client interactions, as well as to study the structure of these potentially very large protein complexes (methyl-TROSY).By exploiting these NMR methodologies and additional, novel labeling schemes, we will characterize, for the first time, the recognition and substrate remodeling performed by the many members of the DnaJ and sHsp chaperone families on their clients. We will then take these approaches one step further and develop real time NMR experiments to observe the client remodeling performed over the course of the disaggregation reaction itself.By combining advanced NMR with biophysical and functional assays, we ultimately aim to identify the specific sets of chaperones that, with the Hsp70 system, protect our cells by dissolving disease-linked aggregates and amyloid fibers. Campo scientifico engineering and technologymaterials engineeringfibersnatural scienceschemical sciencesinorganic chemistrytransition metalsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencescell biologynatural sciencesphysical sciencesopticsspectroscopyabsorption spectroscopy Parole chiave Protein NMR spectroscopy molecular chaperons protein disaggregation Programma(i) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Argomento(i) ERC-2018-STG - ERC Starting Grant Invito a presentare proposte ERC-2018-STG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-STG - Starting Grant Istituzione ospitante WEIZMANN INSTITUTE OF SCIENCE Contribution nette de l'UE € 1 499 956,00 Indirizzo HERZL STREET 234 7610001 Rehovot Israele Mostra sulla mappa Tipo di attività 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 € 1 499 956,00 Beneficiari (1) Classifica in ordine alfabetico Classifica per Contributo netto dell'UE Espandi tutto Riduci tutto WEIZMANN INSTITUTE OF SCIENCE Israele Contribution nette de l'UE € 1 499 956,00 Indirizzo HERZL STREET 234 7610001 Rehovot Mostra sulla mappa Tipo di attività 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 € 1 499 956,00
