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J-domain proteins promote client relay from Hsp70 during tail-anchored membrane protein targeting

Cho, Hyunju and Shim, Woo Jun and Liu, Yumeng and Shan, Shu-ou (2021) J-domain proteins promote client relay from Hsp70 during tail-anchored membrane protein targeting. Journal of Biological Chemistry, 296 . Art. No. 100546. ISSN 0021-9258. doi:10.1016/j.jbc.2021.100546.

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J-domain proteins (JDPs) play essential roles in Hsp70 function by assisting Hsp70 in client trapping and regulating the Hsp70 ATPase cycle. Here, we report that JDPs can further enhance the targeting competence of Hsp70-bound client proteins during tail-anchored protein (TA) biogenesis. In the guided-entry-of-tail–anchored protein pathway in yeast, nascent TAs are captured by cytosolic Hsp70 and sequentially relayed to downstream chaperones, Sgt2 and Get3, for delivery to the ER. We found that two JDPs, Ydj1 and Sis1, function in parallel to support TA targeting to the ER in vivo. Biochemical analyses showed that, while Ydj1 and Sis1 differ in their ability to assist Hsp70 in TA trapping, both JDPs enhance the transfer of Hsp70-bound TAs to Sgt2. The ability of the JDPs to regulate the ATPase cycle of Hsp70 is essential for enhancing the transfer competence of Hsp70-bound TAs in vitro and for supporting TA insertion in vivo. These results demonstrate a role of JDPs in regulating the conformation of Hsp70-bound clients during membrane protein biogenesis.

Item Type:Article
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URLURL TypeDescription
Cho, Hyunju0000-0001-7393-657X
Shim, Woo Jun0000-0001-9596-7393
Shan, Shu-ou0000-0002-6526-1733
Alternate Title:JDPs enhance client relay from Hsp70
Additional Information:© 2021 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license ( Received 22 January 2021, Revised 22 February 2021, Accepted 15 March 2021, Available online 17 March 2021. We thank D. Rapaport, T. Jores for the yeast strains, E. A. Craig for yeast strains and for antibodies against Ssa and Sis1, the Center for Molecular Medicine (California Institute of Technology) for use of the Li-Cor Odyssey imager, and members of the Shan laboratories for critical comments on the manuscript. Data availability: All data described are contained in the manuscript. Author contributions: H. C. and S. S. designed experiments; H. C., W. J. S., and Y. L. performed experiments and analyzed the data; H. C. and S. S. wrote the paper. All authors reviewed the results and approved the final version of the manuscript. Funding and additional information: This work was supported by NIH grant R01 GM107368 and R35 GM136321 to S. S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conflict of interest: The authors declare that they have no conflicts of interest with the contents of this article.
Funding AgencyGrant Number
NIHR01 GM107368
NIHR35 GM136321
Subject Keywords:molecular chaperone; Hsp70; Hsp40; tail-anchored protein; membrane proteins; protein targeting
Record Number:CaltechAUTHORS:20210317-150527513
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Official Citation:Hyunju Cho, Woo Jun Shim, Yumeng Liu, Shu-ou Shan, J-domain proteins promote client relay from Hsp70 during tail-anchored membrane protein targeting, Journal of Biological Chemistry, Volume 296, 2021, 100546, ISSN 0021-9258, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108470
Deposited By: Tony Diaz
Deposited On:19 Mar 2021 18:49
Last Modified:19 Apr 2021 21:36

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