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

被引：205

作者：

Burgos, Patricia V. ^{[1
]}

Mardones, Gonzalo A. ^{[1
]}

Rojas, Adriana L. ^{[2
]}

daSilva, Luis L. P. ^{[1
]}

Prabhu, Yogikala ^{[1
]}

Hurley, James H. ^{[2
]}

Bonifacino, Juan S. ^{[1
]}

机构：

[1] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA

[2] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA

来源：

DEVELOPMENTAL CELL | 2010年 / 18卷 / 03期

关键词：

TRANS-GOLGI NETWORK; BETA-PROTEIN; STRUCTURAL EXPLANATION; SECRETASE CLEAVAGE; SIGNALS; CLATHRIN; SUBUNIT; BINDING; PHOSPHORYLATION; SPECIFICITY;

D O I：

10.1016/j.devcel.2010.01.015

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：425 / 436

页数：12

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