Phosphorylation Regulates Intracellular Trafficking of β-Secretase

β-Secretase (BACE) is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid β-peptide. Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-05, Vol.276 (18), p.14634-14641
Main Authors: Walter, Jochen, Fluhrer, Regina, Hartung, Bianka, Willem, Michael, Kaether, Christoph, Capell, Anja, Lammich, Sven, Multhaup, Gerd, Haass, Christian
Format: Article
Language:English
Subjects:
Amyloid Precursor Protein Secretases
Animals
Aspartic Acid Endopeptidases - metabolism
Casein Kinases
Cell Line
Cytoplasm - metabolism
Endocytosis
Endopeptidases
endosomes
Humans
Phosphorylation
Protein Kinases - metabolism
protein trafficking
Protein Transport
Subcellular Fractions - enzymology
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Summary:β-Secretase (BACE) is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid β-peptide. Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and complex N-glycosylation. Phosphorylation/dephosphorylation affects the subcellular localization of BACE. BACE wild type and an S498D mutant that mimics phosphorylated BACE are predominantly located within juxtanuclear Golgi compartments and endosomes, whereas nonphosphorylatable BACE S498A accumulates in peripheral EEA1-positive endosomes. Antibody uptake assays revealed that reinternalization of BACE from the cell surface is independent of its phosphorylation state. After reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later endosomal compartments and/or the trans-Golgi network. In contrast, nonphosphorylatable BACE S498A is retained within early endosomes. Our results therefore demonstrate regulated trafficking of BACE within the secretory and endocytic pathway.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M011116200