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Monitoring cotranslational protein folding in mammalian cells at codon resolution.


ABSTRACT: 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.

SUBMITTER: Han Y 

PROVIDER: S-EPMC3411940 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Monitoring cotranslational protein folding in mammalian cells at codon resolution.

Han Yan Y   David Alexandre A   Liu Botao B   Magadán Javier G JG   Bennink Jack R JR   Yewdell Jonathan W JW   Qian Shu-Bing SB  

Proceedings of the National Academy of Sciences of the United States of America 20120716 31


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 resoluti  ...[more]

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