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.
| Authors/Editors: |
Miesbauer M Pfeiffer NV Rambold AS Müller V Kiachopoulos S Winklhofer KF |
|---|---|
| Publication Date: | 2009 |
| 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.
