期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 18, 页码 5012-5017出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1519124113
关键词
NMR spectroscopy; ribosome; nascent chain; alpha-synuclein; cotranslational folding
资金
- Wellcome Trust [094425/Z/10/Z, 097806/Z/11/Z]
- Alpha-1 Foundation
- Motor Neurone Disease Association
- Biotechnology and Biochemical Sciences Research Council [BBG0156511]
- MRC [MC_U117533887] Funding Source: UKRI
- Wellcome Trust [097806/Z/11/Z] Funding Source: Wellcome Trust
- Medical Research Council [MC_U117533887] Funding Source: researchfish
- The Francis Crick Institute [10029] Funding Source: researchfish
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 alpha-synuclein (alpha Syn), 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 alpha Syn 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.
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