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

• Published in: Traffic (Copenhagen, Denmark) Vol. 11; no. 2; pp. 250 - 258
• Main Authors: Fassler, Matthias, Zocher, Michael, Klare, Sebastian, de la Fuente, Alerie Guzman, Scheuermann, Johanna, Capell, Anja, Haass, Christian, Valkova, Christina, Veerappan, Anbazhagan, Schneider, Dirk, Kaether, Christoph
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.02.2010; Blackwell Publishing Ltd
• Subjects: Alzheimer disease; Alzheimer's disease; Amyloid Precursor Protein Secretases - chemistry; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Cell Line; Endoplasmic Reticulum - metabolism; ER retention/retrieval; Humans; Immunoblotting; Mice; Microscopy, Fluorescence; presenilin; Presenilins - chemistry; Presenilins - genetics; Protein Binding; Protein Sorting Signals; Protein Structure, Tertiary; Protein Transport; transmembrane domain; γ-secretase
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/j.1600-0854.2009.01014.x

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.