Sorting of the Alzheimer's Disease Amyloid Precursor Protein Mediated by the AP-4 Complex

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2010 Mar 17

PMID 20230749

Citations 135

Authors

Patricia V Burgos

Gonzalo A Mardones

Adriana L Rojas

Luis L P daSilva

Yogikala Prabhu

James H Hurley

Juan S Bonifacino

Affiliations

Soon will be listed here.

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 mu4 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 mu4 are distinct from those of other signal-adaptor interactions. Disruption of the APP-AP-4 interaction decreases localization of APP to endosomes and enhances gamma-secretase-catalyzed cleavage of APP to the pathogenic amyloid-beta 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.

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