Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies
Autor: | Elke Deuerling, Sheena E. Radford, Nadine Sachs, Patrick D. Knight, Judith Frydman, Renate Schlömer, Lukas Leiendecker, Martin Gamerdinger, Karina Gense, Antonio N. Calabrese, Koning Shen, Ankit Baghel, Rebecca Chan, Esther M. Martin, Katie L. Stewart |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Protein Folding
Protein subunit Biology Protein aggregation organismal fitness Protein Aggregation Pathological Article protein aggregation 03 medical and health sciences 0302 clinical medicine Protein Domains ddc:570 chaperone Humans Spinocerebellar Ataxias Luciferase Luciferases Molecular Biology polyglutamine (PolyQ) proteins 030304 developmental biology 0303 health sciences proteostasis Amyloid beta-Peptides Binding Sites proteotoxicity Cell Biology Aβ40 age-related proteinopathies 3. Good health Cell biology Huntington Disease Proteostasis nascent polypeptide-associated complex Proteotoxicity Protein Biosynthesis Chaperone (protein) biology.protein Peptides Ribosomes 030217 neurology & neurosurgery Biogenesis Molecular Chaperones Protein Binding Binding domain |
Zdroj: | Molecular Cell |
ISSN: | 1097-2765 |
Popis: | Summary The nascent polypeptide-associated complex (NAC) is a conserved ribosome-associated protein biogenesis factor. Whether NAC exerts chaperone activity and whether this function is restricted to de novo protein synthesis is unknown. Here, we demonstrate that NAC directly exerts chaperone activity toward structurally diverse model substrates including polyglutamine (PolyQ) proteins, firefly luciferase, and Aβ40. Strikingly, we identified the positively charged ribosome-binding domain in the N terminus of the βNAC subunit (N-βNAC) as a major chaperone entity of NAC. N-βNAC by itself suppressed aggregation of PolyQ-expanded proteins in vitro, and the positive charge of this domain was critical for this activity. Moreover, we found that NAC also exerts a ribosome-independent chaperone function in vivo. Consistently, we found that a substantial fraction of NAC is non-ribosomal bound in higher eukaryotes. In sum, NAC is a potent suppressor of aggregation and proteotoxicity of mutant PolyQ-expanded proteins associated with human diseases like Huntington’s disease and spinocerebellar ataxias. Graphical Abstract Highlights • The protein biogenesis factor NAC exhibits broad-spectrum chaperone activity • NAC exerts a ribosome-independent chaperone function • The positively charged N terminus of βNAC is a central chaperone entity of NAC • NAC suppresses aggregation and toxicity of disease-related polyglutamine proteins NAC is a conserved protein biogenesis factor. Shen et al. demonstrate that NAC acts as a chaperone suppressing aggregation and toxicity of human disease-related polyglutamine-expanded proteins. They identify the positively charged domain of βNAC as the critical chaperone domain and show that NAC also acts independent of its ribosome association. |
Databáze: | OpenAIRE |
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