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Mechanical force releases nascent chain–mediated ribosome arrest in vitro and in vivo

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Science  24 Apr 2015:
Vol. 348, Issue 6233, pp. 457-460
DOI: 10.1126/science.1261909

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Force to unblock a clogged ribosome

The synthesis of proteins from mRNA by the ribosome is highly regulated. But newly synthesized protein chains can still block the ribosome exit tunnel and slow protein synthesis. Goldman et al. use optical tweezers to show that by pulling on the stuck protein chain, they can unblock a clogged exit tunnel (see the Perspective by Puglisi). In vivo, the folding of a nascent protein chain just outside the tunnel also generates enough force to unclog a block, indicating that ribosome-peptide interactions fine-tune protein synthesis.

Science, this issue p. 457; see also p. 399

Abstract

Protein synthesis rates can affect gene expression and the folding and activity of the translation product. Interactions between the nascent polypeptide and the ribosome exit tunnel represent one mode of regulating synthesis rates. The SecM protein arrests its own translation, and release of arrest at the translocon has been proposed to occur by mechanical force. Using optical tweezers, we demonstrate that arrest of SecM-stalled ribosomes can indeed be rescued by force alone and that the force needed to release stalling can be generated in vivo by a nascent chain folding near the ribosome tunnel exit. We formulate a kinetic model describing how a protein can regulate its own synthesis by the force generated during folding, tuning ribosome activity to structure acquisition by a nascent polypeptide.

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