Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published June 23, 2015 | Published + Supplemental Material
Journal Article Open

Regulation by a chaperone improves substrate selectivity during cotranslational protein targeting


The ribosome exit site is a crowded environment where numerous factors contact nascent polypeptides to influence their folding, localization, and quality control. Timely and accurate selection of nascent polypeptides into the correct pathway is essential for proper protein biogenesis. To understand how this is accomplished, we probe the mechanism by which nascent polypeptides are accurately sorted between the major cotranslational chaperone trigger factor (TF) and the essential cotranslational targeting machinery, signal recognition particle (SRP). We show that TF regulates SRP function at three distinct stages, including binding of the translating ribosome, membrane targeting via recruitment of the SRP receptor, and rejection of ribosome-bound nascent polypeptides beyond a critical length. Together, these mechanisms enhance the specificity of substrate selection into both pathways. Our results reveal a multilayered mechanism of molecular interplay at the ribosome exit site, and provide a conceptual framework to understand how proteins are selected among distinct biogenesis machineries in this crowded environment.

Additional Information

© 2015 National Academy of Sciences. Edited by Jonathan S. Weissman, University of California, San Francisco, Howard Hughes Medical Institute, and California Institute for Quantitative Biosciences, San Francisco, CA, and approved May 5, 2015 (received for review November 25, 2014). Published online before print June 8, 2015. We thank Xin Zhang and Kuang Shen for insightful discussions, and Harris Bernstein and members of the S.-o.S. group for comments on the manuscript. This work was supported by National Institutes of Health (NIH) Grant GM078024 to S.-o.S. and the NIH NIGMS Ruth L. Kirschstein National Research Service Award (F31GM095294) to A.A. This project was funded in part by the Henry Dreyfus Teacher-Scholar Award, the Packard and Lucile Fellowship in science and engineering, and the Gordon and Betty Moore Foundation through Grant GBMF2939 (to S.-o.S.). Author contributions: A.A., J.H.L., and S.-o.S. designed research; A.A., J.H.L., S.W., I.S., and S.-o.S. performed research; A.A., J.H.L., S.W., I.S., and S.-o.S. analyzed data; and A.A. and S.-o.S. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1422594112/-/DCSupplemental.

Attached Files

Published - PNAS-2015-Ariosa-E3169-78.pdf

Supplemental Material - pnas.201422594SI.pdf


Files (2.6 MB)
Name Size Download all
724.0 kB Preview Download
1.9 MB Preview Download

Additional details

August 22, 2023
October 23, 2023