title: Masking of transmembrane-based retention signals controls ER export of gamma-secretase.
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.
authors: Leibniz Institut für Altersforschung-Fritz Lipmann Institut, 07743 Jena, Germany.
authors: Matthias
authors: M
authors: Fassler
authors: Michael
authors: M
authors: Zocher
authors: Sebastian
authors: S
authors: Klare
authors: Alerie Guzman
authors: AG
authors: de la Fuente
authors: Johanna
authors: J
authors: Scheuermann
authors: Anja
authors: A
authors: Capell
authors: Christian
authors: C
authors: Haass
authors: Christina
authors: C
authors: Valkova
authors: Anbazhagan
authors: A
authors: Veerappan
authors: Dirk
authors: D
authors: Schneider
authors: Christoph
authors: C
authors: Kaether
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008856:Microscopy, Fluorescence; D053763:Presenilins / Q000737:chemistry / Q000235:genetics; D011485:Protein Binding; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: D053763:Presenilins; D021382:Protein Sorting Signals; D053829:Amyloid Precursor Protein Secretases