Amyloid beta protein precursor (AbetaPP), but not AbetaPP-like protein 2, is bridged to the kinesin light chain by the scaffold protein JNK-interacting protein 1.
Proteolytic processing of amyloid beta protein precursor (AbetaPP) generates peptides that regulate normal cell signaling and are implicated in Alzheimer's disease pathogenesis. AbetaPP processing also occurs in nerve processes where AbetaPP is transported from the cell body by kinesin-I, a microtubule motor composed of two kinesin heavy chain and two kinesin light chain (Klc) subunits. AbetaPP transport is supposedly mediated by the direct AbetaPP-Klc1 interaction. Here we demonstrate that the AbetaPP-Klc1 interaction is not direct but is mediated by JNK-interacting protein 1 (JIP1). The phosphotyrosine binding domain of JIP1 binds the cytoplasmic tail of AbetaPP, whereas the JIP1 C-terminal region interacts with the tetratrico-peptide repeats of Klc1. We also show that JIP1 does not bridge the AbetaPP gene family member AbetaPP-like protein 2, APLP2, to Klc1. These results support a model where JIP1 mediates the interaction of AbetaPP to the motor protein kinesin-I and that this JIP1 function is unique for AbetaPP relative to its family member APLP2. Our data suggest that kinesin-I-dependent neuronal AbetaPP transport, which controls AbetaPP processing, may be regulated by JIP1.
Matsuda
Shuji
S
Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, New York 10461, USA.
Matsuda
Yukiko
Y
D'Adamio
Luciano
L
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D016547:Kinesins; D008164:Luminescent Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D019000:Phosphotyrosine / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011498:Protein Precursors; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D015398:Signal Transduction; D014162:Transfection; D020798:Two-Hybrid System Techniques
C489697:APLP1 protein, human; C084104:APLP2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; D002352:Carrier Proteins; C000715688:KLC1 protein, human; C000715695:Kns2 protein, mouse; D008164:Luminescent Proteins; C490666:MAPK8IP1 protein, human; C490665:Mapk8ip protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D019000:Phosphotyrosine; D005982:Glutathione Transferase; D016547:Kinesins