Masking of Transmembrane‐Based Retention Signals Controls ER Export of γ‐Secretase |
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| Authors: | 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 |
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| Institution: | 1. Leibniz Institut für Altersforschung‐Fritz Lipmann Institut, 07743 Jena, Germany;2. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ludwig‐Maximilians‐Universit?t München, Adolf Butenandt Institute, 80336 München, Germany;3. Present address: European Molecular Biology Laboratory, 69117 Heidelberg, Germany;4. Institut für Biochemie und Molekularbiologie, ZBMZ, Albert‐Ludwigs‐Universit?t, 79104 Freiburg, Germany |
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| Abstract: | 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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| Keywords: | Alzheimer's disease ER retention/retrieval presenilin γ ‐secretase transmembrane domain |
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