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Published February 10, 2009 | Supplemental Material + Published
Journal Article Open

Multiple conformational switches in a GTPase complex control co-translational protein targeting


The "GTPase switch" paradigm, in which a GTPase switches between an active, GTP-bound state and an inactive, GDP-bound state through the recruitment of nucleotide exchange factors (GEFs) or GTPase activating proteins (GAPs), has been used to interpret the regulatory mechanism of many GTPases. A notable exception to this paradigm is provided by two GTPases in the signal recognition particle (SRP) and the SRP receptor (SR) that control the co-translational targeting of proteins to cellular membranes. Instead of the classical "GTPase switch," both the SRP and SR undergo a series of discrete conformational rearrangements during their interaction with one another, culminating in their reciprocal GTPase activation. Here, we show that this series of rearrangements during SRP-SR binding and activation provide important control points to drive and regulate protein targeting. Using real-time fluorescence, we showed that the cargo for SRP—ribosomes translating nascent polypeptides with signal sequences—accelerates SRP·SR complex assembly over 100-fold, thereby driving rapid delivery of cargo to the membrane. A series of subsequent rearrangements in the SRP·SR GTPase complex provide important driving forces to unload the cargo during late stages of protein targeting. Further, the cargo delays GTPase activation in the SRP·SR complex by 8–12 fold, creating an important time window that could further improve the efficiency and fidelity of protein targeting. Thus, the SRP and SR GTPases, without recruiting external regulatory factors, constitute a self-sufficient system that provides exquisite spatial and temporal control of a complex cellular process.

Additional Information

© 2009 by the National Academy of Sciences. Edited by Jennifer A. Doudna, University of California, Berkeley, CA, and approved December 22, 2008 (received for review August 28, 2008). We thank Sandra Schmid, Douglas C. Rees, Raymond Deshaies, Nathan Pierce, and members of the Shan laboratory for comments on the manuscript. This work was supported by a National Institutes of Health grant GM078024 to S.S., and by the Swiss National Science Foundation (SNSF) and the NCCR Structural Biology program of the SNSF to N.B. S.S. was supported by a career award from the Burroughs Welcome Foundation, the Henry and Camille Dreyfus foundation, the Beckman Young Investigator award, and the Packard and Lucile award in science and engineering. X.Z. was supported by a fellowship from the Ulric B. and Evelyn L. Bray Endowment Fund.

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Published - ZHApnas09.pdf

Supplemental Material - ZHApnas09supp.pdf


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