alpha-Helical domains promote translocation of intrinsically disordered polypeptides into the endoplasmic reticulum.
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.
Miesbauer
Margit
M
Neurobiochemistry, Deutsches Zentrum für Neurodegenerative Erkrankungen and Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, D-80336 München, Germany.
Pfeiffer
Natalie V
NV
Rambold
Angelika S
AS
Müller
Veronika
V
Kiachopoulos
Sophia
S
Winklhofer
Konstanze F
KF
Tatzelt
Jörg
J
D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport
C057074:Plfr protein, mouse; D011257:Pregnancy Proteins; D021382:Protein Sorting Signals