TY - JOUR
T1 - Masking of transmembrane-based retention signals controls ER export of gamma-secretase
AU - Fassler, Matthias
AU - Zocher, Michael
AU - Klare, Sebastian
AU - de la Fuente, Alerie Guzman
AU - Scheuermann, Johanna
AU - Capell, Anja
AU - Haass, Christian
AU - Valkova, Christina
AU - Veerappan, Anbazhagan
AU - Schneider, Dirk
AU - Kaether, Christoph
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
KW - Amyloid Precursor Protein Secretases/chemistry
KW - Animals
KW - Cell Line
KW - Endoplasmic Reticulum/metabolism
KW - Humans
KW - Immunoblotting
KW - Mice
KW - Microscopy, Fluorescence
KW - Presenilins/chemistry
KW - Protein Binding
KW - Protein Sorting Signals
KW - Protein Structure, Tertiary
KW - Protein Transport
U2 - 10.1111/j.1600-0854.2009.01014.x
DO - 10.1111/j.1600-0854.2009.01014.x
M3 - Article
C2 - 19958468
SN - 1398-9219
VL - 11
SP - 250
EP - 258
JO - Traffic
JF - Traffic
IS - 2
ER -