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Structural characterization of the interaction of α-synuclein nascent chains with the ribosomal surface and trigger factor

Deckert, A; Waudby, CA; Wlodarski, T; Wentink, AS; Wang, X; Kirkpatrick, JP; Paton, JF; ... Christodoulou, J; + view all (2016) Structural characterization of the interaction of α-synuclein nascent chains with the ribosomal surface and trigger factor. Proceedings of the National Academy of Sciences of the United States of America , 113 (18) pp. 5012-5017. 10.1073/pnas.1519124113. Green open access

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Abstract

The ribosome is increasingly becoming recognized as a key hub for integrating quality control processes associated with protein biosynthesis and cotranslational folding (CTF). The molecular mechanisms by which these processes take place, however, remain largely unknown, in particular in the case of intrinsically disordered proteins (IDPs). To address this question, we studied at a residue-specific level the structure and dynamics of ribosome-nascent chain complexes (RNCs) of α-synuclein (αSyn), an IDP associated with Parkinson's disease (PD). Using solution-state nuclear magnetic resonance (NMR) spectroscopy and coarse-grained molecular dynamics (MD) simulations, we find that, although the nascent chain (NC) has a highly disordered conformation, its N-terminal region shows resonance broadening consistent with interactions involving specific regions of the ribosome surface. We also investigated the effects of the ribosome-associated molecular chaperone trigger factor (TF) on αSyn structure and dynamics using resonance broadening to define a footprint of the TF-RNC interactions. We have used these data to construct structural models that suggest specific ways by which emerging NCs can interact with the biosynthesis and quality control machinery.

Type: Article
Title: Structural characterization of the interaction of α-synuclein nascent chains with the ribosomal surface and trigger factor
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1519124113
Publisher version: http://dx.doi.org/10.1073/pnas.1519124113
Language: English
Additional information: Copyright © 2016 National Academy of Sciences.
Keywords: NMR spectroscopy, cotranslational folding, nascent chain, ribosome, α-synuclein
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/1482748
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