期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 31, 页码 12467-12472出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1208138109
关键词
deep sequencing; ribosome profiling; protein quality
资金
- National Institute of Allergy and Infectious Diseases Division of Intramural Research
- National Institutes of Health Grant [1DP2 OD006449-01]
- Ellison Medical Foundation Grant [AG-NS-0605-09]
- US Department of Defense Exploration-Hypothesis Development Award [TS10078]
How the ribosome-bound nascent chain folds to assume its functional tertiary structure remains a central puzzle in biology. In contrast to refolding of a denatured protein, cotranslational folding is complicated by the vectorial nature of nascent chains, the frequent ribosome pausing, and the cellular crowdedness. Here, we present a strategy called folding-associated cotranslational sequencing that enables monitoring of the folding competency of nascent chains during elongation at codon resolution. By using an engineered multidomain fusion protein, we demonstrate an efficient cotranslational folding immediately after the emergence of the full domain sequence. We also apply folding-associated cotranslational sequencing to track cotranslational folding of hemagglutinin in influenza A virus-infected cells. In contrast to sequential formation of distinct epitopes, the receptor binding domain of hemagglutinin follows a global folding route by displaying two epitopes simultaneously when the full sequence is available. Our results provide direct evidence of domain-wise global folding that occurs cotranslationally in mammalian cells.
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