Abstract
About one-quarter to nearly one-third of the proteins synthesized in the cytosol of eukaryotic cells are integrated into the plasma membrane or are secreted. Translocation of secretory proteins into the lumen of the endoplasmic reticulum or the periplasm of bacteria is mediated by a highly conserved heterotrimeric membrane protein complex denoted Sec61 in eukaryotes and SecYEG in bacteria. To evaluate a possible modulation of the translocation efficiency by secondary structures of the nascent peptide chain, we performed a comparative analysis in bacteria, yeast, and mammalian cells. Strikingly, neither the bacterial SecY nor the eukaryotic Sec61 translocon was able to efficiently transport proteins entirely composed of intrinsically disordered domains (IDDs) or β-strands. However, translocation could be restored by α-helical domains in a position- and organism-dependent manner. In bacteria, we found that the α-helical domains have to precede the IDD or β-strands, whereas in mammalian cells, C-terminally located α-helical domains are sufficient to promote translocation. Our study reveals an evolutionarily conserved deficiency of the Sec61/SecY complex to translocate IDDs and β-strands in the absence of α-helical domains. Moreover, our results may suggest that adaptive pathways co-evolved with the expansion of IDDs in the proteome of eukaryotic cells to increase the transport capacity of the Sec61 translocon.
Highlights
About one-quarter to nearly one-third of the proteins synthesized in the cytosol of eukaryotic cells are integrated into the plasma membrane or are secreted
We and others demonstrated that intrinsically disordered proteins (IDPs) equipped with authentic N-terminal endoplasmic reticulum (ER) signal peptides failed to be productively imported into the ER lumen of neuronal cells [31,32,33,34,35]
Previous studies revealed that productive ER import of IDPs equipped with authentic N-terminal ER signal peptides is greatly impaired in mammalian cells [31, 32, 34, 35]
Summary
About one-quarter to nearly one-third of the proteins synthesized in the cytosol of eukaryotic cells are integrated into the plasma membrane or are secreted. We and others demonstrated that intrinsically disordered proteins (IDPs) equipped with authentic N-terminal ER signal peptides failed to be productively imported into the ER lumen of neuronal cells [31,32,33,34,35]. This might be related to the lack of structural elements, which have been shown to already form within the ribosomal tunnel and to modulate the translocation process (36 – 46). Our study may indicate the evolution of auxiliary translocon components in eukaryotes to expand the transport capacity of the Sec complex for secretory proteins with extended unstructured domains
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