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Receptor compaction and GTPase movements drive cotranslational protein translocation

Lee, Jae Ho and Chung, SangYoon and Hwang Fu, Yu-Hsien and Qian, Ruilin and Sun, Xuemeng and Weiss, Shimon and Shan, Shu-ou (2020) Receptor compaction and GTPase movements drive cotranslational protein translocation. . (Unpublished)

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Signal recognition particle (SRP) is a universally conserved targeting machine that couples the synthesis of ~30% of the proteome to their proper membrane localization. In eukaryotic cells, SRP recognizes translating ribosomes bearing hydrophobic signal sequences and, through interaction with SRP receptor (SR), delivers them to the Sec61p translocase on the endoplasmic reticulum (ER) membrane. How SRP ensures efficient and productive initiation of protein translocation at the ER is not well understood. Here, single molecule fluorescence spectroscopy demonstrates that cargo-loaded SRP induces a global compaction of SR, driving a >90 Å movement of the SRP·SR GTPase complex from the vicinity of the ribosome exit, where it initially assembles, to the distal site of SRP. These rearrangements bring translating ribosomes near the membrane, expose conserved Sec61p docking sites on the ribosome and weaken SRP's interaction with the signal sequence on the nascent polypeptide, thus priming the translating ribosome for engaging the translocation machinery. Disruption of these rearrangements severely impairs cotranslational protein translocation and is the cause of failure in an SRP54 mutant linked to severe congenital neutropenia. Our results demonstrate that multiple largescale molecular motions in the SRP·SR complex are required to drive the transition from protein targeting to translocation; these post-targeting rearrangements provide potential new points for biological regulation as well as disease intervention.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Chung, SangYoon0000-0002-0592-4099
Hwang Fu, Yu-Hsien0000-0002-2861-4843
Weiss, Shimon0000-0002-0720-5426
Shan, Shu-ou0000-0002-6526-1733
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. bioRxiv preprint first posted online Jan. 8, 2020. We thank S. Chandrasekar and H. Hsieh for sharing reagents, A. Jomaa and N. Ban for helpful discussions, and members of the Shan lab for comments on the manuscript. This work was supported by National Institutes of Health grant GM078024 and the Gordon and Betty Moore Foundation through grant GBMF2939 to S.-o. Shan, and by National Institutes of Health grant GM130942 and Dean Willard Chair funds to S.W. AUTHOR CONTRIBUTIONS. J.L., Y.H., and S.S. designed research; J.L., Y.H., R.Q, and X.S. performed biochemical experiments and analyzed data; J.L., R.Q., and S.C. performed μs-ALEX experiments and analyzed data; S.W. provided guidance for μs-ALEX analysis; J.L. and S.S. wrote the manuscript with input from S.C. and S.W.
Funding AgencyGrant Number
Gordon and Betty Moore FoundationGBMF2939
Dean Willard ChairUNSPECIFIED
Subject Keywords:Protein Targeting, Signal Recognition Particle, Single Molecule Spectroscopy, GTPase, Ribosome, Protein Dynamics
Record Number:CaltechAUTHORS:20200109-143242552
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Official Citation:Receptor compaction and GTPase movements drive cotranslational protein translocation Jae Ho Lee, SangYoon Chung, Yu-Hsien Hwang Fu, Ruilin Qian, Xuemeng Sun, Shimon Weiss, Shu-ou Shan bioRxiv 2020.01.07.897827; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100603
Deposited By: George Porter
Deposited On:10 Jan 2020 15:19
Last Modified:10 Jan 2020 15:19

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