Molecular mechanism and structure of Trigger Factor bound to the translating ribosome

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Abstract
Ribosome‐associated chaperone Trigger Factor (TF) initiates folding of newly synthesized proteins in bacteria. Here, we pinpoint by site‐specific crosslinking the sequence of molecular interactions of Escherichia coli TF and nascent chains during translation. Furthermore, we provide the first full‐length structure of TF associated with ribosome–nascent chain complexes by using cryo‐electron microscopy. In its active state, TF arches over the ribosomal exit tunnel accepting nascent chains in a protective void. The growing nascent chain initially follows a predefined path through the entire interior of TF in an unfolded conformation, and even after folding into a domain it remains accommodated inside the protective cavity of ribosome‐bound TF. The adaptability to accept nascent chains of different length and folding states may explain how TF is able to assist co‐translational folding of all kinds of nascent polypeptides during ongoing synthesis. Moreover, we suggest a model of how TF's chaperoning function can be coordinated with the co‐translational processing and membrane targeting of nascent polypeptides by other ribosome‐associated factors.