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

Xin Zhang, Christiane Schaffitzel, Nenad Ban, Shu Ou Shan

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1754-1759
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number6
DOIs
StatePublished - Feb 10 2009

All Science Journal Classification (ASJC) codes

  • General

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