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Published July 28, 2017 | Published
Journal Article Open

Two-step membrane binding by the bacterial SRP receptor enable efficient and accurate Co-translational protein targeting


The signal recognition particle (SRP) delivers ~30% of the proteome to the eukaryotic endoplasmic reticulum, or the bacterial plasma membrane. The precise mechanism by which the bacterial SRP receptor, FtsY, interacts with and is regulated at the target membrane remain unclear. Here, quantitative analysis of FtsY-lipid interactions at single-molecule resolution revealed a two-step mechanism in which FtsY initially contacts membrane via a Dynamic mode, followed by an SRP-induced conformational transition to a Stable mode that activates FtsY for downstream steps. Importantly, mutational analyses revealed extensive auto-inhibitory mechanisms that prevent free FtsY from engaging membrane in the Stable mode; an engineered FtsY pre-organized into the Stable mode led to indiscriminate targeting in vitro and disrupted FtsY function in vivo. Our results show that the two-step lipid-binding mechanism uncouples the membrane association of FtsY from its conformational activation, thus optimizing the balance between the efficiency and fidelity of co-translational protein targeting.

Additional Information

© 2017 Hwang Fu et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 12 February 2017; Accepted: 28 June 2017; Published: 28 July 2017. We thank Connie Wang and members of the Shan lab for critical discussions and comments on the manuscript; Wen-Chen Lin, and Meredith Triplet from the Groves lab for the helps on SLB techniques; Oliver Loson from the Chan lab alumni for help on checking the SLB quality; Heun Jin Lee and Tal Einav from the Phillips Lab for helping us set up real-time delivery instruments and for modeling discussions, respectively. This work was supported by NIH grant GM078024 and the Gordon and Betty Moore Foundation through Grant GBMF2939 to SS. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Author Contributions: Y-HHF, Conceptualization, Data curation, Software, Formal analysis, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing; WYCH, Validation, Methodology, Writing—review and editing; KS, Validation, Investigation, Methodology, Writing—review and editing; JTG, Resources, Supervision, Validation, Methodology, Writing—review and editing; TM, Formal analysis, Methodology, Writing—review and editing; S-oS, Conceptualization, Formal analysis, Supervision, Funding acquisition, Visualization, Writing—review and editing. The authors declare that no competing interests exist.

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