Novel Human Chaperone Mechanisms Counteracting Protein Misfolding and Aggregation in the Cell

Descripción del proyecto

Desvelar los secretos de los defensores celulares de las proteínas

El mal plegamiento y la agregación de proteínas amenazan la salud celular, lo que contribuye a enfermedades como la neurodegeneración, las miopatías y los trastornos metabólicos. Las chaperonas moleculares, en particular la diversa familia de proteínas de dominio J (JDP, por sus siglas en inglés), desempeñan un papel fundamental en la protección de las células al prevenir e invertir el mal plegamiento de las proteínas. Sin embargo, los mecanismos a través de los cuales las JDP desempeñan sus funciones esenciales siguen siendo poco conocidos, lo que limita los avances terapéuticos. En descubrimientos recientes se ha descubierto la sorprendente complejidad de las JDP, incluidos nuevos mecanismos de regulación y reconocimiento de proteínas. En este contexto, el equipo del proyecto CHARM, financiado por el Consejo Europeo de Investigación, desvelará los mecanismos estructurales y funcionales de las JDP de seres humanos mediante resonancia magnética nuclear metil-TROSY de última generación y ensayos biofísicos instantáneos. Al descifrar las funciones dinámicas de estas chaperonas, en CHARM se pretende avanzar en el tratamiento de las enfermedades relacionadas con el mal plegamiento de las proteínas.

Objetivo

MolecuMolecular chaperones are vital for maintaining proteostasis by protecting our cells from the deleterious effects of protein misfolding and aggregation. The diverse ~50-chaperone J-domain protein (JDP, Hsp40) family acts as cells first line of defense, binding and remodeling non-natively folded proteins and facilitating their transfer to downstream chaperones. Recent discoveries from our lab have shown that JDP function is far more complex than previously described - identifying both a novel mode of regulation by which DNAJB1 coordinates amyloid disaggregation, and a new mechanism by which class A JDPs recognize destabilized proteins.
Based on these findings and the sheer diversity of human JDPs, we propose that these chaperones employ many additional, yet-to-be-discovered mechanisms to carry out their vital cellular roles. Obtaining a structural and functional understanding of these chaperones is further crucial, as mutations in JDPs have been linked to many pathologies, including myopathies, neurodegenerative diseases, and metabolic disorders. Here we aim to uncover these novel JDP functional mechanisms, determine their role in addressing diverse proteomic challenges, and characterize how their malfunction leads to disease.
Study of JDPs has proven challenging due to the dynamic nature of these chaperones, their transient interactions with clients, and the instability of misfolded proteins. The advanced methyl-TROSY NMR techniques used in my lab are, however, ideally suited for such large and dynamic systems. Furthermore, we have developed new NMR and biophysical assays allowing the monitoring of chaperone interactions with misfolded and aggregation-prone substrates in real time.
Using these approaches, this project will unveil the structures and functional mechanisms of the diverse human JDPs, introducing fundamental new concepts into the chaperone field and paving the way for therapeutic strategies targeting protein misfolding and aggregation diseases.