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The Metastable XBP1u transmembrane domain defines determinants for intramembrane proteolysis by signal peptide peptidase

Summary - Unspliced XBP1 mRNA encodes XBP1u, the transcriptionally inert variant of the unfolded protein response (UPR) transcription factor XBP1s. XBP1u targets its mRNA-ribosome-nascent-chain-complex to the endoplasmic reticulum (ER) to facilitate UPR activation and prevents overactivation. Yet, i...

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Hauptverfasser: Lipp, Sara Suna (VerfasserIn) , Lorenzoni, Alessandra (VerfasserIn) , Lemberg, Marius (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: March 12, 2019
In: Cell reports
Year: 2019, Jahrgang: 26, Heft: 11, Pages: 3087-3099, e1-e11
ISSN:2211-1247
DOI:10.1016/j.celrep.2019.02.057
Online-Zugang:Verlag, Volltext: https://doi.org/10.1016/j.celrep.2019.02.057
Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S2211124719302360
Volltext
Verfasserangaben:Sara Suna Yücel, Walter Stelzer, Alessandra Lorenzoni, Manfred Wozny, Dieter Langosch, and Marius K. Lemberg
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Zusammenfassung:Summary - Unspliced XBP1 mRNA encodes XBP1u, the transcriptionally inert variant of the unfolded protein response (UPR) transcription factor XBP1s. XBP1u targets its mRNA-ribosome-nascent-chain-complex to the endoplasmic reticulum (ER) to facilitate UPR activation and prevents overactivation. Yet, its membrane association is controversial. Here, we use cell-free translocation and cellular assays to define a moderately hydrophobic stretch in XBP1u that is sufficient to mediate insertion into the ER membrane. Mutagenesis of this transmembrane (TM) region reveals residues that facilitate XBP1u turnover by an ER-associated degradation route that is dependent on signal peptide peptidase (SPP). Furthermore, the impact of these mutations on TM helix dynamics was assessed by residue-specific amide exchange kinetics, evaluated by a semi-automated algorithm. Based on our results, we suggest that SPP-catalyzed intramembrane proteolysis of TM helices is not only determined by their conformational flexibility, but also by side-chain interactions near the scissile peptide bond with the enzyme’s active site.
Beschreibung:Gesehen am 24.04.2019
Beschreibung:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2019.02.057

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