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.