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

Patricia V. Burgos, Gonzalo A. Mardones, Adriana L. Rojas, Luis L.P. daSilva, Yogikala Prabhu, James H. Hurley, Juan S. Bonifacino*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

209 Scopus citations

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 languageEnglish
Pages (from-to)425-436
Number of pages12
JournalDevelopmental Cell
Volume18
Issue number3
DOIs
StatePublished - 2010
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2010 Elsevier Inc.

ASJC Scopus subject areas

  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • Developmental Biology
  • Cell Biology

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