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Masking of Transmembrane-Based Retention Signals Controls ER Export of γ-Secretase

  1. Matthias Fassler1,
  2. Michael Zocher1,
  3. Sebastian Klare1,
  4. Alerie Guzman De La Fuente1,
  5. Johanna Scheuermann2,3,
  6. Anja Capell2,
  7. Christian Haass2,
  8. Christina Valkova1,
  9. Anbazhagan Veerappan4,
  10. Dirk Schneider4,
  11. Christoph Kaether1,*

Article first published online: 5 NOV 2009

DOI: 10.1111/j.1600-0854.2009.01014.x

Issue

Traffic

Traffic

Volume 11, Issue 2, pages 250–258, February 2010

Additional Information

How to Cite

Fassler, M., Zocher, M., Klare, S., De La Fuente, A. G., Scheuermann, J., Capell, A., Haass, C., Valkova, C., Veerappan, A., Schneider, D. and Kaether, C. (2010), Masking of Transmembrane-Based Retention Signals Controls ER Export of γ-Secretase. Traffic, 11: 250–258. doi: 10.1111/j.1600-0854.2009.01014.x

Author Information

  1. 1

    Leibniz Institut für Altersforschung-Fritz Lipmann Institut, 07743 Jena, Germany

  2. 2

    Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ludwig-Maximilians-Universität München, Adolf Butenandt Institute, 80336 München, Germany

  3. 3

    Present address: European Molecular Biology Laboratory, 69117 Heidelberg, Germany

  4. 4

    Institut für Biochemie und Molekularbiologie, ZBMZ, Albert-Ludwigs-Universität, 79104 Freiburg, Germany

*Christoph Kaether, ckaether@fli-leibniz.de

Publication History

  1. Issue published online: 4 JAN 2010
  2. Article first published online: 5 NOV 2009
  3. Received 9 June 2009, revised and accepted for publication 3 November 2009, uncorrected manuscript published online 5 November 2009, published online 2 December 2009

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Keywords:

  • Alzheimer's disease;
  • ER retention/retrieval;
  • presenilin;
  • γ-secretase;
  • transmembrane domain

γ-Secretase is critically involved in the Notch pathway and in Alzheimer's disease. The four subunits of γ-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 γ-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 γ-secretase complex could mask TMD-based ER-retention/retrieval signals to allow plasma membrane transport of fully assembled γ-secretase.

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