Alpha-helical domains promote translocation of intrinsically disordered polypeptides into the endoplasmic reticulum
J Biol Chem. 2009 Sep 4;284(36):24384-93. Epub 2009 Jun 26.
|Type of Publication:||Journal Article|
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/pre-emptive pathway. Productive ER import could be reinstated by increasing the amount of alpha-helical domains, while more effective ER-signal sequences had only a minor effect on ER import efficiency of unstructured polypeptides. ER stress and over-expression 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, pre-emptive quality control pathway.