Sorting of the Alzheimer's Disease Amyloid Precursor Protein Mediated by the AP-4 Complex
- NIH
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 {micro}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 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.
- Research Organization:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1002576
- Journal Information:
- Dev. Cell, Journal Name: Dev. Cell Journal Issue: (3) ; 03, 2010 Vol. 18
- Country of Publication:
- United States
- Language:
- ENGLISH
Similar Records
Overproduction, purification, crystallization and preliminary X-ray analysis of human Fe65-PTB2 in complex with the amyloid precursor protein intracellular domain
CD147 is a regulatory subunit of the gamma-secretase complex inAlzheimer's disease amyloid beta-peptide production
Effects of presenilin-1 familial Alzheimer’s disease mutations on γ-secretase activation for cleavage of amyloid precursor protein
Journal Article
·
Thu May 01 00:00:00 EDT 2008
· Acta Crystallographica. Section F
·
OSTI ID:22360578
CD147 is a regulatory subunit of the gamma-secretase complex inAlzheimer's disease amyloid beta-peptide production
Journal Article
·
Wed Apr 06 00:00:00 EDT 2005
· Proceedings of the National Academy of Sciences of the United States of America
·
OSTI ID:861515
Effects of presenilin-1 familial Alzheimer’s disease mutations on γ-secretase activation for cleavage of amyloid precursor protein
Journal Article
·
Mon Feb 13 19:00:00 EST 2023
· Communications Biology
·
OSTI ID:2422941