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

Burgos, PV; Mardones, GA; Rojas, AL; Dasilva, LLP; Prabhu, Y; Hurley, JH; Bonifacino, JS

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 mu 4 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 mu 4 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.

Más información

Título según WOS: Sorting of the Alzheimer's Disease Amyloid Precursor Protein Mediated by the AP-4 Complex
Título de la Revista: DEVELOPMENTAL CELL
Volumen: 18
Número: 3
Editorial: Cell Press
Fecha de publicación: 2010
Página de inicio: 425
Página final: 436
Idioma: English
DOI:

10.1016/j.devcel.2010.01.015

Notas: ISI