Developmental Cell
Volume 18, Issue 3, 16 March 2010, Pages 425-436
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Article
Sorting of the Alzheimer's Disease Amyloid Precursor Protein Mediated by the AP-4 Complex

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Summary

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.

Highlights

► A sorting signal in the cytosolic tail of APP interacts with the μ4 subunit of AP-4 ► X-ray crystallography reveals that the APP signal binds to a distinct site on μ4 ► Disruption of the APP-AP-4 interaction decreases APP localization to endosomes ► Redistribution of APP enhances γ-secretase-mediated cleavage to amyloid-β peptide

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These authors contributed equally to this work