Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 52, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2103015118
Keywords
cotranslational folding; NMR spectroscopy; structural biology; alpha synuclein; in-cell NMR
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Funding
- Motor Neurone Disease Association
- Francis Crick Institute
- Wellcome Trust [206409/Z/17/Z]
- Wellcome Trust [206409/Z/17/Z] Funding Source: Wellcome Trust
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The study reveals that interactions on the surface of ribosomes in cells determine the dynamics of emerging disordered polypeptides, with specific basic and aromatic motifs affecting these interactions and competing with trigger factors, while also guiding the direction of nascent chains. The ribosome acts as a scaffold with holdase characteristics, facilitating handover of nascent chains to specific auxiliary proteins in the cytosol.
In the cell, the conformations of nascent polypeptide chains during translation are modulated by both the ribosome and its associated molecular chaperone, trigger factor. The specific interactions that underlie these modulations, however, are still not known in detail. Here, we combine protein engineering, in-cell and in vitro NMR spectroscopy, and molecular dynamics simulations to explore how proteins interact with the ribosome during their biosynthesis before folding occurs. Our observations of alpha-synuclein nascent chains in living Escherichia coli cells reveal that ribosome surface interactions dictate the dynamics of emerging disordered polypeptides in the crowded cytosol. We show that specific basic and aromatic motifs drive such interactions and directly compete with trigger factor binding while biasing the direction of the nascent chain during its exit out of the tunnel. These results reveal a structural basis for the functional role of the ribosome as a scaffold with holdase characteristics and explain how handover of the nascent chain to specific auxiliary proteins occurs among a host of other factors in the cytosol.
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