Project description
Chaperone-mediated attack of protein aggregates
Protein folding is paramount for proper protein function and is assisted by other proteins known as molecular chaperones. Emerging evidence suggests that chaperones also break down protein aggregates seen during neurodegeneration in Alzheimer's, Parkinson's and Huntington's diseases. However, it remains unclear how these chaperones perform this disaggregation function. The EU-funded NMR-DisAgg project aims to study the mechanisms of chaperone interactions, overcoming the challenges associated with the dynamic and short-lived nature of these encounters. Delineation of the disaggregation reaction will offer a better view of the process of degeneration and potentially identify novel therapeutic targets.
Objective
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.
Fields of science
- engineering and technologymaterials engineeringfibers
- natural scienceschemical sciencesinorganic chemistrytransition metals
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- natural sciencesphysical sciencesopticsspectroscopyabsorption spectroscopy
Programme(s)
Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
7610001 Rehovot
Israel