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Semisynthetic Modification of Tau Protein with Di-Ubiquitin Chains for Aggregation Studies

Ubiquitin, a protein modifier that regulates diverse essential cellular processes, is also a component of the protein inclusions characteristic of many neurodegenerative disorders. In Alzheimer’s disease, the microtubule associated tau protein accumulates within damaged neurons in the form of cross-...

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Detalles Bibliográficos
Autores principales: Munari, Francesca, Barracchia, Carlo Giorgio, Parolini, Francesca, Tira, Roberto, Bubacco, Luigi, Assfalg, Michael, D’Onofrio, Mariapina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352214/
https://www.ncbi.nlm.nih.gov/pubmed/32575755
http://dx.doi.org/10.3390/ijms21124400
Descripción
Sumario:Ubiquitin, a protein modifier that regulates diverse essential cellular processes, is also a component of the protein inclusions characteristic of many neurodegenerative disorders. In Alzheimer’s disease, the microtubule associated tau protein accumulates within damaged neurons in the form of cross-beta structured filaments. Both mono- and polyubiquitin were found linked to several lysine residues belonging to the region of tau protein that forms the structured core of the filaments. Thus, besides priming the substrate protein for proteasomal degradation, ubiquitin could also contribute to the assembly and stabilization of tau protein filaments. To advance our understanding of the impact of ubiquitination on tau protein aggregation and function, we applied disulfide-coupling chemistry to modify tau protein at position 353 with Lys48- or Lys63-linked di-ubiquitin, two representative polyubiquitin chains that differ in topology and structure. Aggregation kinetics experiments performed on these conjugates reveal that di-ubiquitination retards filament formation and perturbs the fibril elongation rate more than mono-ubiquitination. We further show that di-ubiquitination modulates tau-mediated microtubule assembly. The effects on tau protein aggregation and microtubule polymerization are essentially independent from polyubiquitin chain topology. Altogether, our findings provide novel insight into the consequences of ubiquitination on the functional activity and disease-related behavior of tau protein.