Control of co‐translational protein targeting by self‐regulating GTPases

Abstract

Co‐translational targeting of proteins to cellular membranes is controlled spatially and temporally by two homologous GTPases in the signal recognition particle (SRP) and the SRP receptor (SR). Intriguingly, SRP and SR represent a growing number of noncanonical GTPases that do not employ the classical 'GTPase switch' mechanism. Instead, we showed that these GTPases undergo a series of discrete conformational changes during their interaction with one another, culminating in reciprocal GTPase activation. Importantly, each conformational change allows SRP and SR to provide a distinct point of regulation during protein targeting. Cargo loading on the SRP and membrane association of SR each accelerates SRP‐SR complex formation over 100‐fold, ensuring the efficient delivery of cargo to the membrane. Subsequent conformational changes in the GTPase complex weakens the affinity of SRP for the cargo, driving the unloading and delivery of cargo to the protein conducting channel. Finally, the cargo also delays GTPase activation in the SRP▸SR complex, creating a valuable time window that can improve the efficiency and fidelity of protein targeting. We propose that the SRP and SR represent a new class of 'self‐regulating' GTPases that can use their intrinsic conformational flexibility to provide the molecular driving force and to improve the fidelity of complex cellular processes.