Abstract
Adaptor protein 4 (AP-4) is the most recently discovered and least well-characterized member of the family of heterotetrameric adaptor protein (AP) complexes that mediate sorting of transmembrane cargo in post-Golgi compartments. Herein, we report the interaction of an YKFFE sequence from the cytosolic tail of the Alzheimer's disease amyloid precursor protein (APP) with the μ4 subunit of AP-4. Biochemical and X-ray crystallographic analyses reveal that the properties of the APP sequence and the location of the binding site on μ4 are distinct from those of other signal-adaptor interactions. Disruption of the APP-AP-4 interaction decreases localization of APP to endosomes and enhances γ-secretase-catalyzed cleavage of APP to the pathogenic amyloid-β peptide. These findings demonstrate that APP and AP-4 engage in a distinct type of signal-adaptor interaction that mediates transport of APP from the trans-Golgi network (TGN) to endosomes, thereby reducing amyloidogenic processing of the protein.
Original language | English |
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Pages (from-to) | 425-436 |
Number of pages | 12 |
Journal | Developmental Cell |
Volume | 18 |
Issue number | 3 |
DOIs | |
State | Published - 2010 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2010 Elsevier Inc.
ASJC Scopus subject areas
- Molecular Biology
- General Biochemistry, Genetics and Molecular Biology
- Developmental Biology
- Cell Biology