Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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

Traffic. 2010 Feb;11(2):250-8. Epub 2009 Nov 5.

Authors/Editors: Fassler M
Zocher M
Klare S
de la Fuente AG
Scheuermann J
Capell A
Haass C
Valkova C
Veerappan A
Schneider D
Kaether C
Publication Date: 2009
Type of Publication: Journal Article
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.

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