Measuring Endoplasmic Reticulum Signal Sequences Translocation Efficiency Using the Xbp1 Arrest Peptide

Cell Chemical Biology
Theresa KrieglerTara Hessa

Abstract

Secretory proteins translocate across the mammalian ER membrane co-translationally via the ribosome-sec61 translocation machinery. Signal sequences within the polypeptide, which guide this event, are diverse in their hydrophobicity, charge, length, and amino acid composition. Despite the known sequence diversity in the ER signals, it is generally assumed that they have a dominant role in determining co-translational targeting and translocation process. We have analyzed co-translational events experienced by secretory proteins carrying efficient versus inefficient signal sequencing, using an assay based on Xbp1 peptide-mediated translational arrest. With this method we were able to measure the functional efficiency of ER signal sequences. We show that an efficient signal sequence experiences a two-phase event whereby the nascent chain is pulled from the ribosome during its translocation, thus resuming translation and yielding full-length products. Conversely, the inefficient signal sequence experiences a single weaker pulling event, suggesting inadequate engagement by the translocation machinery of these marginally hydrophobic signal sequences.

Citations

May 27, 2020·Open Biology·Antonietta Russo
Apr 18, 2020·The FEBS Journal·Sarah O'Keefe, Stephen High
Oct 27, 2020·Journal of Biomolecular Structure & Dynamics·Giovanna De SimonePaolo Ascenzi
Jun 6, 2020·Journal of Molecular Biology·Theresa KrieglerTara Hessa
May 8, 2021·The FEBS Journal·Sarah O'KeefeStephen High
Aug 27, 2021·Nature Communications·Doyeon KimDaehyun Baek
Oct 13, 2021·ChemPlusChem·Ziqi Lyu, Joseph C Genereux

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