Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I.
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.
Kamal
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A
Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla 92093, USA.
Stokin
G B
GB
Yang
Z
Z
Xia
C H
CH
Goldstein
L S
LS
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000235:genetics / Q000502:physiology*; D001667:Binding, Competitive / Q000235:genetics; D015153:Blotting, Western; D001923:Brain Chemistry; D002499:Centrifugation, Density Gradient; D000939:Epitopes / Q000378:metabolism; D018390:Gene Targeting; D016547:Kinesins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000737:chemistry / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D000939:Epitopes; C000715695:Kns2 protein, mouse; D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; D016547:Kinesins