Masking of transmembrane-based retention signals controls ER export of gamma-secretase

Matthias Fassler, Michael Zocher, Sebastian Klare, Alerie Guzman de la Fuente, Johanna Scheuermann, Anja Capell, Christian Haass, Christina Valkova, Anbazhagan Veerappan, Dirk Schneider, Christoph Kaether

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

gamma-Secretase is critically involved in the Notch pathway and in Alzheimer's disease. The four subunits of gamma-secretase assemble in the endoplasmic reticulum (ER) and unassembled subunits are retained/retrieved to the ER by specific signals. We here describe a novel ER-retention/retrieval signal in the transmembrane domain (TMD) 4 of presenilin 1, a subunit of gamma-secretase. TMD4 also is essential for complex formation, conferring a dual role for this domain. Likewise, TMD1 of Pen2 is bifunctional as well. It carries an ER-retention/retrieval signal and is important for complex assembly by binding to TMD4. The two TMDs directly interact with each other and mask their respective ER-retention/retrieval signals, allowing surface transport of reporter proteins. Our data suggest a model how assembly of Pen2 into the nascent gamma-secretase complex could mask TMD-based ER-retention/retrieval signals to allow plasma membrane transport of fully assembled gamma-secretase.

Original languageEnglish
Pages (from-to)250-8
Number of pages9
JournalTraffic
Volume11
Issue number2
DOIs
Publication statusPublished - Feb 2010

Keywords

  • Amyloid Precursor Protein Secretases/chemistry
  • Animals
  • Cell Line
  • Endoplasmic Reticulum/metabolism
  • Humans
  • Immunoblotting
  • Mice
  • Microscopy, Fluorescence
  • Presenilins/chemistry
  • Protein Binding
  • Protein Sorting Signals
  • Protein Structure, Tertiary
  • Protein Transport

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