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J Biol Chem. 2009 Sep 4;284(36):24384-93. doi: 10.1074/jbc.M109.023135. Epub 2009 Jun 26.

alpha-Helical domains promote translocation of intrinsically disordered polypeptides into the endoplasmic reticulum.

Author information

1
Neurobiochemistry, Deutsches Zentrum für Neurodegenerative Erkrankungen and Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, D-80336 München, Germany.

Abstract

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 alpha-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 p58(IPK) 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.

PMID:
19561072
PMCID:
PMC2782031
DOI:
10.1074/jbc.M109.023135
[Indexed for MEDLINE]
Free PMC Article

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