Global Rearrangement of SRP Regulates Co‐translational Protein Targeting

The Signal Recognition Particle (SRP) and its receptor (SR) are GTPases responsible for targeting ribosome‐nascent chain complexes (RNCs) to cellular membranes, and are essential for the structure and functional of all cells. When loaded the RNC, SRP forms a complex with SR to bring the RNC to the membrane, and subsequent rearrangements in this complex activate GTP hydrolysis and upload the RNC onto the translocon. During protein targeting, the SRP RNA plays an essential role in accelerating both SRP‐SR complex formation and GTP hydrolysis. Here we show that the SRP RNA is a bi‐functional molecule with two distinct functional ends, the tetraloop end and the distal end, that each stimulates the SRP‐SR complex formation and GTP hydrolysis steps at distinct stages of protein targeting. These results, together with direct visualization using single molecule techniques, demonstrate that the SRP‐SR GTPase complex travels over 100 Angstrom in the targeting reaction, from the RNA's tetraloop end during initial complex assembly to its distal end during GTPase activation. This rearrangement is regulated by the RNC and the translocon. The large‐scale movement of the GTPase complex provides an attractive molecular mechanism for coupling GTPase activation to the transfer of RNC from SRP to the translocon, thereby ensuring efficient and productive protein targeting.