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The presenilin C‐terminus is required for ER‐retention, nicastrin‐binding and γ‐secretase activity
Author(s) -
Kaether Christoph,
Capell Anja,
Edbauer Dieter,
Winkler Edith,
Novak Bozidar,
Steiner Harald,
Haass Christian
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600478
Subject(s) - nicastrin , biology , presenilin , c terminus , microbiology and biotechnology , biochemistry , alzheimer's disease , medicine , disease , amino acid
γ‐Secretase is an intramembrane cleaving protease involved in Alzheimer's disease. γ‐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 γ‐secretase assembly. Here we demonstrate that the cytoplasmic tail of PS1 fulfills several functions required for complex formation, retention of unincorporated PS1 and γ‐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 γ‐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 γ‐secretase complex, suggesting that at least a part of the retention motif may also be required for the function of PS1.