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Journal Article

α-Helical Domains Promote Translocation of Intrinsically Disordered Polypeptides into the Endoplasmic Reticulum


Rambold,  Angelika
Department of Developmental Immunobiology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Miesbauer, M., Pfeiffer, N. V., Rambold, A., Müller, V., Kiachopoulos, S., Winklhofer, K. F., et al. (2009). α-Helical Domains Promote Translocation of Intrinsically Disordered Polypeptides into the Endoplasmic Reticulum. The Journal of Biological Chemistry, 284, 24384-24393. doi:10.1074/jbc.M109.023135.

Cite as: https://hdl.handle.net/21.11116/0000-0007-8BE4-B
Co-translational import into the endoplasmic reticulum (ER) is primarily controlled by N-terminal signal sequences that mediate targeting of the ribosome-nascent chain complex to the Sec61/translocon and initiate the translocation process. Here we show that after targeting to the translocon the secondary structure of the nascent polypeptide chain can significantly modulate translocation efficiency. ER-targeted polypeptides dominated by unstructured domains failed to efficiently translocate into the ER lumen and were subjected to proteasomal degradation via a co-translocational/preemptive pathway. Productive ER import could be reinstated by increasing the amount of α-helical domains, whereas more effective ER signal sequences had only a minor effect on ER import efficiency of unstructured polypeptides. ER stress and overexpression of p58IPK promoted the co-translocational degradation pathway. Moreover polypeptides with unstructured domains at their N terminus were specifically targeted to proteasomal degradation under these conditions. Our study indicates that extended unstructured domains are signals to dispose ER-targeted proteins via a co-translocational, preemptive quality control pathway.