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. Author manuscript; available in PMC: 2023 Nov 30.
Published in final edited form as: J Mol Biol. 2022 Sep 19;434(22):167832. doi: 10.1016/j.jmb.2022.167832

Figure 10. Early events at the ribosome as a response to a lost nascent chain interaction with SRP.

Figure 10.

The figure shows a hypothetical model demonstrating RAPP activation and engagement of specific chaperones, ubiquitination and ribosome rearrangement as a result of the lost SRP interactions with polypeptide nascent chains. During normal protein synthesis (scenario 1) SRP co-translationally binds signal sequence of the exposed nascent chain, pauses the translation and targets the ribosome-nascent chain complex to the SRP receptor in the ER membrane. Then ribosome-nascent chain complex is transferred to the Sec61 translocon releasing SRP. Translation is resumed, and the protein is co-translationally translocated into ER lumen, and the signal sequence is cleaved off by a signal peptidase (not shown in the figure). If interactions with SRP are lost due to defects in SRP (scenario 2) or mutations in the signal sequence of the nascent chain (scenario 3), the cells respond to this failure by activation of the RAPP pathway engaging AGO2 (not shown). This triggers upregulation of the distinct chaperones (heat shock proteins), forming specific chaperone network to prevent aggregation of the partly synthesized aberrant peptides and provide help in their clearance. The RAPP activation also triggers K48-linked ubiquitination (Ub). It may affect the ribosomal proteins facilitating the ribosome recycling, as well as label aberrant polypeptides for degradation by proteasome. Ribosomes undergo rearrangement due to decrease of the RPS27 and increase RPS27L proteins during the stress induced by the SRP54 depletion. RPS27L could potentially substitute RPS27 in effort to restore or maintain the translation activity of the ribosomes during stress. Finally, mRNAs of secretory and membrane proteins are degraded by engagement of still unidentified nuclease(s). Partly synthesized nascent polypeptides are degraded by proteasome to prevent their accumulation in the cytoplasm. Ribosome subunits 40S, 60S, and translating mRNA are marked in light purple, dark purple and brown color, correspondingly, SRP is in yellow, nascent chain is in blue, signal sequence is in dark blue, defective signal sequence is shown in red, SRP receptor subunits SRa and SRb are in light and dark green, correspondingly, Sec61 translocon is in orange-brown.