Description du projet
Attaque des agrégats de protéines par les chaperons
Le repliement des protéines est primordial pour leur bon fonctionnement et le processus est aidé par d’autres protéines appelées chaperons moléculaires. De nouvelles preuves laissent penser que les chaperons décomposent également les agrégats de protéines observés au cours de la neurodégénérescence dans les maladies d’Alzheimer, de Parkinson et de Huntington. Cependant, la manière dont ces chaperons remplissent cette fonction de désagrégation n’est toujours pas clairement établie. Le projet NMR-DisAgg, financé par l’UE, vise à étudier les mécanismes des interactions entre chaperons, en surmontant les difficultés liées à la nature dynamique et éphémère de ces rencontres. La délimitation de la réaction de désagrégation permettra de mieux comprendre le processus de dégénérescence et d’identifier de nouvelles cibles thérapeutiques.
Objectif
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.
Champ scientifique
- natural scienceschemical sciencesinorganic chemistrytransition metals
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- natural sciencesphysical sciencesopticsspectroscopyabsorption spectroscopy
- natural sciencesbiological sciencesgeneticsmutation
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
7610001 Rehovot
Israël