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Abstract

Cellular proteins begin to fold as they emerge from the ribosome.The folding landscape of nascent chains is not only shaped by theiramino acid sequence but also by the interactions with the ribo-some. Here, we combine biophysical methods with cryo-EM struc-ture determination to show that folding of aβ-barrel proteinbegins with formation of a dynamicα-helix inside the ribosome. Asthe growing peptide reaches the end of the tunnel, the N-terminalpart of the nascent chain refolds to aβ-hairpin structure thatremains dynamic until its release from the ribosome. Contactswith the ribosome and structure of the peptidyl transferase centerdepend on nascent chain conformation. These results indicate thatproteins may start out asα-helices inside the tunnel and switchinto their native folds only as they emerge from the ribosome.Moreover, the correlation of nascent chain conformations withreorientation of key residues of the ribosomal peptidyl-transferasecenter suggest that protein folding could modulate ribosome activity.