Article
- The EMBO Journal (2004) 23, 4738 - 4748
- doi:10.1038/sj.emboj.7600478
Published online: 18 November 2004
Subject Categories:
The presenilin C-terminus is required for ER-retention, nicastrin-binding and 
-secretase activity
Christoph Kaether, Anja Capell, Dieter Edbauer, Edith Winkler, Bozidar Novak, Harald Steiner and Christian Haass
- Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-Universität, München, Germany
Correspondence to:
Christian Haass, Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Schillerstr. 44, 80336 München, Germany. Tel.: +49 89 218075 471/472; Fax: +49 89 218075 415; E-mail: chaass@med.uni-muenchen.de
Christoph Kaether, Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Schillerstr. 44, 80336 München, Germany. Tel.: +49 89 218075 471/472; Fax: +49 89 218075 415; E-mail: ckaether@med.uni-muenchen.de
Received 31 March 2004; Accepted 15 October 2004
Abstract
-Secretase is an intramembrane cleaving protease involved in Alzheimer's disease. -Secretase occurs as a high molecular weight complex composed of presenilin (PS1/2), nicastrin (NCT), anterior pharynx-defective phenotype 1 and PS enhancer 2. Little is known about the cellular mechanisms of -secretase assembly. Here we demonstrate that the cytoplasmic tail of PS1 fulfills several functions required for complex formation, retention of unincorporated PS1 and -secretase activity. The very C-terminus interacts with the transmembrane domain of NCT and may penetrate into the membrane. Deletion of the last amino acid is sufficient to completely block -secretase assembly and release of PS1 from the endoplasmic reticulum (ER). This suggests that unincorporated PS1 is actively retained within the ER. We identified a hydrophobic stretch of amino acids within the cytoplasmic tail of PS1 distinct from the NCT-binding site, which is required to retain unincorporated PS1 within the ER. Deletion of the retention signal results in the release of PS1 from the ER and the assembly of a nonfunctional -secretase complex, suggesting that at least a part of the retention motif may also be required for the function of PS1.
Keywords:
- Alzheimer's disease,
- amyloid precursor protein,
- nicastrin,
- presenilin,
- -secretase
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