Masking of transmembrane-based retention signals controls ER export of gamma-secretase.
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.
Fassler
Matthias
M
Leibniz Institut für Altersforschung-Fritz Lipmann Institut, 07743 Jena, Germany.
Zocher
Michael
M
Klare
Sebastian
S
de la Fuente
Alerie Guzman
AG
Scheuermann
Johanna
J
Capell
Anja
A
Haass
Christian
C
Valkova
Christina
C
Veerappan
Anbazhagan
A
Schneider
Dirk
D
Kaether
Christoph
C
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
D053763:Presenilins; D021382:Protein Sorting Signals; D053829:Amyloid Precursor Protein Secretases