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Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
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Structural features of the KPI domain control APP dimerization, trafficking, and processing.

Naouel Ben Khalifa1, Donatienne Tyteca, Claudia Marinangeli

  • 1Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.

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PubMed
Summary

The Kunitz-type protease inhibitor (KPI) domain in APP751 significantly enhances amyloid precursor protein (APP) homodimerization, influencing its trafficking and processing. This dimerization is crucial for directing APP through the secretory pathway and promoting non-amyloidogenic processing.

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Area of Science:

  • Molecular Biology
  • Neuroscience
  • Cell Biology

Background:

  • Two major human amyloid precursor protein (APP) isoforms, APP695 and APP751, exist.
  • APP751 contains a Kunitz-type protease inhibitor (KPI) domain absent in APP695.
  • APP homodimerization is believed to regulate its processing and function.

Purpose of the Study:

  • To investigate the role of APP isoforms and the KPI domain in APP homodimerization.
  • To determine how APP dimerization affects its subcellular localization and processing.
  • To elucidate the regulatory mechanisms of APP trafficking and function.

Main Methods:

  • Bimolecular fluorescence complementation (BiFC) was employed to study APP isoform dimerization.
  • Mutational analysis of dimerization motifs and the KPI domain was performed.
  • Subcellular localization of APP dimers was assessed using microscopy.
  • APP processing pathways were analyzed.

Main Results:

  • APP751 exhibited significantly higher homodimerization compared to APP695.
  • The native folding of the KPI domain was critical for APP751 homodimerization.
  • APP dimers were primarily localized in the Golgi region within the secretory pathway.
  • KPI domain mutation caused APP homodimer retention in the endoplasmic reticulum.
  • APP751 demonstrated more efficient non-amyloidogenic processing than APP695.

Conclusions:

  • The KPI domain plays a crucial role in regulating APP homodimerization.
  • APP dimerization influences its subcellular localization and trafficking within the secretory pathway.
  • Dimerization acts as a key regulator of APP processing, impacting its functional outcomes.