Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies

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2019
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Shen, Koning
Chan, Rebecca
Martin, Esther M.
Knight, Patrick D.
Leiendecker, Lukas
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Molecular cell. 2019, 74(4), pp. 729-741.e7. ISSN 1097-2765. eISSN 1097-4164. Available under: doi: 10.1016/j.molcel.2019.03.012
Zusammenfassung

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.

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ISO 690SHEN, Koning, Martin GAMERDINGER, Rebecca CHAN, Karina GENSE, Esther M. MARTIN, Nadine SACHS, Patrick D. KNIGHT, Renate SCHLÖMER, Lukas LEIENDECKER, Elke DEUERLING, 2019. Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies. In: Molecular cell. 2019, 74(4), pp. 729-741.e7. ISSN 1097-2765. eISSN 1097-4164. Available under: doi: 10.1016/j.molcel.2019.03.012
BibTex
@article{Shen2019-05-16Ribos-46297,
  year={2019},
  doi={10.1016/j.molcel.2019.03.012},
  title={Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies},
  number={4},
  volume={74},
  issn={1097-2765},
  journal={Molecular cell},
  pages={729--741.e7},
  author={Shen, Koning and Gamerdinger, Martin and Chan, Rebecca and Gense, Karina and Martin, Esther M. and Sachs, Nadine and Knight, Patrick D. and Schlömer, Renate and Leiendecker, Lukas and Deuerling, Elke}
}
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    <dcterms:abstract xml:lang="eng">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.</dcterms:abstract>
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