The eukaryotic signal-recognition particle 54 (SRP54; Ffh in prokaryotes) and its receptor SRα (FtsY in prokaryotes) are GTPases that directly interact during the co-translational targeting of proteins to the endoplasmic-reticulum membrane (or plasma membrane in prokaryotes). On complex formation, these proteins stimulate each other's GTPase activity to induce GTP hydrolysis, which ensures the unidirectional targeting of the nascent protein through a pore in the membrane. But how does this reciprocal activation occur? Papers in Nature and Science — by Stroud and colleagues and Freymann and co-workers, respectively — now provide insights into this process by reporting crystal structures of a complex of Ffh, FtsY and a non-hydrolysable GTP analogue (GMPPCP).
The structures highlight a symmetrical heterodimer that has an extensive interaction interface, and show that complex formation produces a composite active site that contains two GMPPCP molecules. Remarkably, the GMPPCP molecules interact directly; such a nucleotide–nucleotide interaction was not expected. By contrast with most other GTPases, there are only small differences between the free GTP- and GDP-bound states of Ffh and FtsY, whereas significant conformational changes occur in these proteins when they interact with each other. The extensive protein interface and the direct nucleotide–nucleotide interaction seen in this complex explain the coordinate activation of these GTPases, and clarify why complex formation is GTP-dependent and GTP hydrolysis leads to complex dissociation. REFERENCES Egea, P. F. et al. Substrate twinning activates the signal recognition particle and its receptor. Nature 427, 215–221 (2004) Focia, P. J. et al. Heterodimeric GTPase core of the SRP targeting complex. Science 303, 373–377 (2004)
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