The signal recognition particle (SRP) is a conserved ribonucleoprotein complex essential for co-translational protein translocation into the endoplasmic reticulum (ER). Among its components, the SRP68/72 heterodimer must play a pivotal role in regulating translation and SRP function, yet not fully understood. Using cryo-electron microscopy (cryo-EM), we present the full-length structure of human SRP68/72, revealing a previously uncharacterised and significantly larger protein-binding domain (PBD) than previously reported.
This extended SRP68/72 PBD forms a stable interface between SRP68 and SRP72 and exhibits RNA-binding activity independent of sequence specificity. Our structural analysis shows that the PBD interacts directly with the Alu domain of the SRP RNA, a region known to mediate elongation arrest during protein targeting. Comparative modeling suggests that upon SRP docking to its receptor, the SRP68/72 PBD undergoes substantial repositioning, facilitating the release of elongation arrest by disengaging the Alu domain and SRP9/14 from the ribosomal surface.
These findings position SRP68/72 as a multifunctional regulator within the SRP complex and stabilising protein-protein interactions, binding RNA, and orchestrating the transition from translation arrest to ER translocation. The lack of sequence specificity in RNA binding suggests a broader regulatory potential extending beyond the SRP role.
Moreover, SRP dysfunction can lead to various human diseases, including cancer, neurodegeneration, and immune disorders. Understanding the structural dynamics and interactions of SRP68/72 may offer new insights into how aberrant protein sorting and translation regulation contribute to each specific disease.