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Receptor compaction and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER

Lee, Jae Ho and Jomaa, Ahmad and Chung, SangYoon and Hwang Fu, Yu-Hsien and Qian, Ruilin and Sun, Xuemeng and Hsieh, Hao-Hsuan and Chandrasekar, Sowmya and Bi, Xiaotian and Mattei, Simone and Boehringer, Daniel and Weiss, Shimon and Ban, Nenad and Shan, Shu-ou (2021) Receptor compaction and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER. Science Advances, 7 (21). Art. No. eabg0942. ISSN 2375-2548. PMCID PMC8139590. doi:10.1126/sciadv.abg0942.

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The conserved signal recognition particle (SRP) cotranslationally delivers ~30% of the proteome to the eukaryotic endoplasmic reticulum (ER). The molecular mechanism by which eukaryotic SRP transitions from cargo recognition in the cytosol to protein translocation at the ER is not understood. Here, structural, biochemical, and single-molecule studies show that this transition requires multiple sequential conformational rearrangements in the targeting complex initiated by guanosine triphosphatase (GTPase)–driven compaction of the SRP receptor (SR). Disruption of these rearrangements, particularly in mutant SRP54G226E linked to severe congenital neutropenia, uncouples the SRP/SR GTPase cycle from protein translocation. Structures of targeting intermediates reveal the molecular basis of early SRP-SR recognition and emphasize the role of eukaryote-specific elements in regulating targeting. Our results provide a molecular model for the structural and functional transitions of SRP throughout the targeting cycle and show that these transitions provide important points for biological regulation that can be perturbed in genetic diseases.

Item Type:Article
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URLURL TypeDescription Materials CentralArticle Paper
Lee, Jae Ho0000-0002-8663-3209
Jomaa, Ahmad0000-0002-5543-7942
Chung, SangYoon0000-0002-0592-4099
Hwang Fu, Yu-Hsien0000-0002-2861-4843
Hsieh, Hao-Hsuan0000-0001-9629-5832
Mattei, Simone0000-0002-2005-8977
Boehringer, Daniel0000-0002-6666-8447
Weiss, Shimon0000-0002-0720-5426
Ban, Nenad0000-0002-9527-210X
Shan, Shu-ou0000-0002-6526-1733
Alternate Title:Receptor compaction and GTPase movements drive cotranslational protein translocation
Additional Information:© 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). Submitted 10 December 2020; Accepted 1 April 2021; Published 21 May 2021. We thank the members of the Shan and Ban laboratory for comments on the manuscript. We thank A. Scaiola for the support with EM data processing and M. Leibundgut for the support with model building. Cryo-EM data were collected at the Scientific Center for Optical and Electron Microscopy at the ETH Zurich (ScopeM). This work was supported by National Institutes of Health grants GM078024 and R35 GM136321, National Science Foundation grant MCB-1929452, and the Gordon and Betty Moore Foundation grant GBMF2939 to S.S.; by the Swiss National Science Foundation (SNSF) (grant number 310030B_163478) and National Center of Excellence in Research (NCCR) RNA and Disease Program of the SNSF (grant number 51NF40_141735) to N.B.; and by National Institutes of Health grant GM130942 and Dean Willard Chair funds to S.W. We gratefully acknowledge the support of NVIDIA Corporation for the Titan Xp GPU used in this research through a GPU Grant program awarded to A.J. Author contributions: J.H.L., A.J., Y.-H.H.F., N.B., and S.S. designed research. J.H.L., Y.-H.H.F., R.Q., X.S., H.-H.H., X.B., and S.C. performed biochemical experiments and analyzed data. A.J. and S.M. purified RNCs for cryo-EM data collection. A.J., S.M., and D.B. collected EM data. A.J. processed cryo-EM data and built atomic models. J.H.L., R.Q., and S.Y.C. performed μs-ALEX experiments and analyzed data. S.W. provided guidance for μs-ALEX analysis. J.H.L., S.S., A.J., and N.B. wrote the manuscript with input from S.C., H.-H.H., S.Y.C. and S.W. Competing interests: S.W. is a consultant to Bio-Rad. The authors declare that they have no other competing interests. Data and materials availability: All the data and associated procedures are described in the manuscript and/or in Supplementary Materials. Cryo-EM maps and model coordinates are deposited in the EMDB as EMD-12303, EMD-12304, and EMD-12305 and in the PDB as PDB ID 7NFX.
Funding AgencyGrant Number
NIHR35 GM136321
Gordon and Betty Moore FoundationGBMF2939
Swiss National Science Foundation (SNSF)310030B_163478
Swiss National Science Foundation (SNSF)51NF40_141735
Dean Willard ChairUNSPECIFIED
Issue or Number:21
PubMed Central ID:PMC8139590
Record Number:CaltechAUTHORS:20200109-143242552
Persistent URL:
Official Citation:J. H. Lee, A. Jomaa, S. Chung, Y.-H. Hwang Fu, R. Qian, X. Sun, H.-H. Hsieh, S. Chandrasekar, X. Bi, S. Mattei, D. Boehringer, S. Weiss, N. Ban, S.-o. Shan, Receptor compaction and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER. Sci. Adv. 7, eabg0942 (2021); DOI: 10.1126/sciadv.abg0942
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:28 May 2021 15:35

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