Sorting of the Alzheimer's disease amyloid precursor protein mediated by the AP-4 complex

Dev Cell. 2010 Mar 16;18(3):425-36. doi: 10.1016/j.devcel.2010.01.015.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Protein Complex 4 / chemistry
  • Adaptor Protein Complex 4 / genetics
  • Adaptor Protein Complex 4 / metabolism*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Binding Sites / genetics
  • Crystallography, X-Ray
  • Endosomes / metabolism
  • HeLa Cells
  • Humans
  • In Vitro Techniques
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Protein Interaction Domains and Motifs
  • Protein Structure, Tertiary
  • Protein Subunits
  • Protein Transport
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction

Substances

  • Adaptor Protein Complex 4
  • Amyloid beta-Protein Precursor
  • Multiprotein Complexes
  • Protein Subunits
  • Recombinant Proteins
  • Amyloid Precursor Protein Secretases

Associated data

  • PDB/3L81