Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I

Neuron. 2000 Nov;28(2):449-59. doi: 10.1016/s0896-6273(00)00124-0.

Abstract

We analyzed the mechanism of axonal transport of the amyloid precursor protein (APP), which plays a major role in the development of Alzheimer's disease. Coimmunoprecipitation, sucrose gradient, and direct in vitro binding demonstrated that APP forms a complex with the microtubule motor, conventional kinesin (kinesin-I), by binding directly to the TPR domain of the kinesin light chain (KLC) subunit. The estimated apparent Kd for binding is 15-20 nM, with a binding stoichiometry of two APP per KLC. In addition, association of APP with microtubules and axonal transport of APP is greatly decreased in a gene-targeted mouse mutant of the neuronally enriched KLC1 gene. We propose that one of the normal functions of APP may be as a membrane cargo receptor for kinesin-I and that KLC is important for kinesin-I-driven transport of APP into axons.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Axonal Transport / genetics
  • Axonal Transport / physiology*
  • Binding, Competitive / genetics
  • Blotting, Western
  • Brain Chemistry
  • Centrifugation, Density Gradient
  • Epitopes / metabolism
  • Gene Targeting
  • Kinesin / metabolism
  • Mice
  • Mice, Mutant Strains
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Microtubules / metabolism
  • Precipitin Tests
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sciatic Nerve / chemistry
  • Sciatic Nerve / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • Epitopes
  • Microtubule-Associated Proteins
  • Recombinant Fusion Proteins
  • kinesin light-chain proteins
  • Kinesin