Abstract
Co-translational protein targeting is an essential, evolutionarily conserved pathway for delivering nascent proteins to the proper cellular membrane. In this pathway, the signal recognition particle (SRP) first recognizes the N-terminal signal sequence of nascent proteins and subsequently interacts with the SRP receptor. For this, signal sequence binding in the SRP54 M domain must be effectively communicated to the SRP54 NG domain that interacts with the receptor. Here we present the 2.9 Å crystal structure of unbound- and signal sequence bound SRP forms, both present in the asymmetric unit. The structures provide evidence for a coupled binding and folding mechanism in which signal sequence binding induces the concerted folding of the GM linker helix, the finger loop, and the C-terminal alpha helix αM6. This mechanism allows for a high degree of structural adaptability of the binding site and suggests how signal sequence binding in the M domain is coupled to repositioning of the NG domain.
Highlights
Co-translational protein targeting is an essential, evolutionarily conserved pathway for delivering nascent proteins to the proper cellular membrane
The amino-acid sequence C-terminal to aM5 in the M domain varies between species in length and composition, but is found in all SRP54 proteins[21]
These residues, which are deleted in most SRP54 constructs used for crystallization, are flexible in the crystal structure of the free Pyrococcus furiosus SRP54
Summary
Co-translational protein targeting is an essential, evolutionarily conserved pathway for delivering nascent proteins to the proper cellular membrane In this pathway, the signal recognition particle (SRP) first recognizes the N-terminal signal sequence of nascent proteins and subsequently interacts with the SRP receptor. The evolutionary conserved SRP core only comprises the SRP54 protein (termed Ffh in bacteria) bound to the coaxial stacked helices 5 and 8 of SRP RNA It is this SRP core that carries out the key functions of signal sequence recognition and SR interaction. Biochemical studies show that the binding of a signal sequence to the M domain accelerates GTP-independent interaction between the NG domain and SR at the helix 8 tetraloop[15,16] This ‘early’ complex undergoes a GTP-dependent structural change that results in a ‘closed’ and stable complex. The N-terminus of a signal sequence typically contains positively charged residues with an as yet unknown function
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