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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / metabolism*
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Axonal Transport / genetics
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Axonal Transport / physiology*
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Binding, Competitive / genetics
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Blotting, Western
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Brain Chemistry
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Centrifugation, Density Gradient
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Epitopes / metabolism
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Gene Targeting
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Kinesins / metabolism
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Mice
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Mice, Mutant Strains
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Microtubules / metabolism
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Precipitin Tests
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Sciatic Nerve / chemistry
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Sciatic Nerve / metabolism
Substances
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Amyloid beta-Protein Precursor
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Epitopes
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Kns2 protein, mouse
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Microtubule-Associated Proteins
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Recombinant Fusion Proteins
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Kinesins