Sorting of the Alzheimer's disease amyloid precursor protein mediated by the AP-4 complex.
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.
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Patricia V
PV
Burgos
Gonzalo A
GA
Mardones
Adriana L
AL
Rojas
Luis L P
LL
daSilva
Yogikala
Y
Prabhu
James H
JH
Hurley
Juan S
JS
Bonifacino
D033964:Adaptor Protein Complex 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D033964:Adaptor Protein Complex 4; D016564:Amyloid beta-Protein Precursor; D046912:Multiprotein Complexes; D021122:Protein Subunits; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases