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Published January 2, 2019 | Accepted Version + Supplemental Material + Published
Journal Article Open

A Chaperone Lid Ensures Efficient and Privileged Client Transfer during Tail-Anchored Protein Targeting


Molecular chaperones play key roles in maintaining cellular proteostasis. In addition to preventing client aggregation, chaperones often relay substrates within a network while preventing off-pathway chaperones from accessing the substrate. Here we show that a conserved lid motif lining the substrate-binding groove of the Get3 ATPase enables these important functions during the targeted delivery of tail-anchored membrane proteins (TAs) to the endoplasmic reticulum. The lid prevents promiscuous TA handoff to off-pathway chaperones, and more importantly, it cooperates with the Get4/5 scaffolding complex to enable rapid and privileged TA transfer from the upstream co-chaperone Sgt2 to Get3. These findings provide a molecular mechanism by which chaperones maintain the pathway specificity of client proteins in the crowded cytosolic environment.

Additional Information

© 2018 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Received 23 June 2018, Revised 20 September 2018, Accepted 7 December 2018, Available online 2 January 2019. We thank J. Chartron for advice on generating yeast strains using CRISPR-Cas9; R.S. Hegde for CaM expression vectors; H. Cho, M. Rao, F. Liang, A. Siegel, and S. Wang for reagents; S. Hematian and the Beckman Institute Laser Resource Center for training and use of circular dichroism spectrometer; M. Rao for initial observations; and members of the Shan laboratory for critical discussions and comments on the manuscript. This work was supported by Dean Willard Chair funds to S.W., NIH grant GM107368, Gordon and Betty Moore Foundation grant GBMF2939, and a fellowship from the Weston Havens Foundation to S.S. Author Contributions: U.S.C. and S.S. designed the research. U.S.C. performed biochemical experiments. U.S.C. analyzed biochemical data with input from S.S. U.S.C. and S.C. performed single-molecule fluorescence experiments. U.S.C. and S.C. analyzed the data with input from S.W. and S.S. U.S.C and S.S. wrote the manuscript. All authors approved the final manuscript. The authors declare no competing interests.

Attached Files

Published - 1-s2.0-S221112471831965X-main.pdf

Accepted Version - nihms-1023701.pdf

Supplemental Material - 1-s2.0-S221112471831965X-mmc1.pdf


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August 22, 2023
October 19, 2023