Descripción del proyecto
Ataque de agregados de proteínas mediado por chaperonas
El plegado de las proteínas es primordial para su correcto funcionamiento y cuenta con la ayuda de otras proteínas, denominadas «chaperonas moleculares». Las nuevas pruebas sugieren que las chaperonas también descomponen los agregados de proteínas que se observan durante la neurodegeneración en las enfermedades de Alzheimer, Parkinson y Huntington. Sin embargo, sigue sin estar claro cómo estas chaperonas realizan esta función de desagregación. El equipo del proyecto NMR-DisAgg, financiado con fondos europeos, tiene como objetivo estudiar los mecanismos de las interacciones de las chaperonas, lo que permitirá superar los retos asociados a la naturaleza dinámica y de corta duración de estos encuentros. La delimitación de la reacción de desagregación ofrecerá una mejor visión del proceso de degeneración y podría identificará nuevas dianas terapéuticas.
Objetivo
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.
Ámbito científico
- engineering and technologymaterials engineeringfibers
- natural scienceschemical sciencesinorganic chemistrytransition metals
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- natural sciencesphysical sciencesopticsspectroscopyabsorption spectroscopy
Palabras clave
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
7610001 Rehovot
Israel