Endoplasmic reticulum retention of the gamma-secretase complex component Pen2 by Rer1.
gamma-Secretase is involved in the production of amyloid beta-peptide, which is the principal component of amyloid plaques in the brains of patients with Alzheimer disease. gamma-Secretase is a complex composed of presenilin (PS), nicastrin, anterior pharynx-defective phenotype 1 (Aph1) and PS enhancer 2 (Pen2). We previously proposed a mechanism of complex assembly by which unassembled subunits are retained in the endoplasmic reticulum (ER) and only the fully assembled complex is exported from the ER. We have now identified Retention in endoplasmic reticulum 1 (Rer1) as a protein that is involved in the retention/retrieval of unassembled Pen2 to the ER. Direct binding of unassembled Pen2 to Rer1 is mediated by the first transmembrane domain of Pen2, and a conserved asparagine in this domain is required. Downregulation of Rer1 leads to increased surface localization of Pen2, whereas overexpression of Rer1 stabilizes unassembled Pen2. To our knowledge, Rer1 is the first identified interaction partner of mammalian transmembrane-based retention/retrieval signals.
Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Center For Integrated Protein Science Munich and Adolf-Butenandt-Institute, Ludwig-Maximilians-Universität, München 80336, Germany. ckaether@fli-leibniz.de
Christoph
C
Kaether
Johanna
J
Scheuermann
Matthias
M
Fassler
Sonja
S
Zilow
Keiro
K
Shirotani
Christina
C
Valkova
Bozidar
B
Novak
Slavomir
S
Kacmar
Harald
H
Steiner
Christian
C
Haass
D033942:Adaptor Proteins, Vesicular Transport; D020816:Amino Acid Motifs; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001216:Asparagine / Q000737:chemistry / Q000235:genetics; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary
D033942:Adaptor Proteins, Vesicular Transport; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C469349:PSENEN protein, human; C109546:RER1 protein, human; D001216:Asparagine; D053829:Amyloid Precursor Protein Secretases