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Mol Cell. 2019 Apr 8. pii: S1097-2765(19)30186-8. doi: 10.1016/j.molcel.2019.03.012. [Epub ahead of print]

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

Author information

1
Department of Biology, Stanford University, Stanford, CA 94305-5430, USA.
2
Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
3
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
4
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. Electronic address: s.e.radford@leeds.ac.uk.
5
Department of Biology, Stanford University, Stanford, CA 94305-5430, USA. Electronic address: jfrydman@stanford.edu.
6
Department of Biology, University of Konstanz, 78457 Konstanz, Germany. Electronic address: elke.deuerling@uni-konstanz.de.

Abstract

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.

KEYWORDS:

Aβ40; age-related proteinopathies; chaperone; nascent polypeptide-associated complex; organismal fitness; polyglutamine (PolyQ) proteins; protein aggregation; proteostasis; proteotoxicity

PMID:
30982745
DOI:
10.1016/j.molcel.2019.03.012
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