Molecular mechanism of cargo recognition and handover by the mammalian signal recognition particle

Creators: Jomaa, Ahmad; Eitzinger, Simon; Zhu, Zikun; Chandrasekar, Sowmya; Kobayashi, Kan; Shan, Shu-ou; Ban, Nenad

Abstract

Co-translational protein targeting to membranes by the signal recognition particle (SRP) is a universally conserved pathway from bacteria to humans. In mammals, SRP and its receptor (SR) have many additional RNA features and protein components compared to the bacterial system, which were recently shown to play regulatory roles. Due to its complexity, the mammalian SRP targeting process is mechanistically not well understood. In particular, it is not clear how SRP recognizes translating ribosomes with exposed signal sequences and how the GTPase activity of SRP and SR is regulated. Here, we present electron cryo-microscopy structures of SRP and SRP·SR in complex with the translating ribosome. The structures reveal the specific molecular interactions between SRP and the emerging signal sequence and the elements that regulate GTPase activity of SRP·SR. Our results suggest the molecular mechanism of how eukaryote-specific elements regulate the early and late stages of SRP-dependent protein targeting.

Additional Information

© 2021 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 21 December 2020, Revised 23 April 2021, Accepted 15 June 2021, Available online 13 July 2021. We thank A. Scaiola and D. Boehringer for the support with EM data processing, M. Leibundgut for the support with model building, and Jae Ho Lee and members of the Ban and Shan groups for discussions and comments on the manuscript. Cryo-EM data were collected at the Scientific Center for Optical and Electron Microscopy at the ETH Zurich (ScopeM). 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. This work was supported by the Swiss National Science Foundation (SNSF) (grant no. 310030B_163478); the National Center of Excellence in Research (NCCR) RNA & Disease Program of the SNSF (grant no. 51NF40_141735), to N.B.; and National Institutes of Health grant GM107368, National Science Foundation grant MCB-1929452, and the Gordon and Betty Moore Foundation through grant GBMF2939 to S.S. Author contributions: A.J., N.B., and S.S. conceived the project. K.K. and A.J. prepared samples for the cryo-EM analysis. A.J. collected the cryo-EM data. A.J. and S.E. performed the reconstruction and model building. S.C. and Z.Z. purified the recombinant human SRP, SR, and performed the biochemical experiments. N.B., S.S., and A.J. supervised the research. A.J., N.B., and S.S. wrote the manuscript. All of the authors interpreted the data and contributed to the final versions of the manuscript. The authors declare no competing interests. N.B. is a member of the Cell Reports advisory board.

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