Chiba Kyoko, Chien Ko-Yi, Sobu Yuriko, Hata Saori, Kato Shun, Nakaya Tadashi, Okada Yasushi, Nairn Angus C, Kinjo Masataka, Taru Hidenori, Wang Rong, Suzuki Toshiharu
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Mol Biol Cell. 2017 Dec 15;28(26):3857-3869. doi: 10.1091/mbc.E17-05-0303. Epub 2017 Nov 1.
In neurons, amyloid β-protein precursor (APP) is transported by binding to kinesin-1, mediated by JNK-interacting protein 1b (JIP1b), which generates the enhanced fast velocity (EFV) and efficient high frequency (EHF) of APP anterograde transport. Previously, we showed that EFV requires conventional interaction between the JIP1b C-terminal region and the kinesin light chain 1 (KLC1) tetratricopeptide repeat, whereas EHF requires a novel interaction between the central region of JIP1b and the coiled-coil domain of KLC1. We found that phosphorylatable Thr466 of KLC1 regulates the conventional interaction with JIP1b. Substitution of Glu for Thr466 abolished this interaction and EFV, but did not impair the novel interaction responsible for EHF. Phosphorylation of KLC1 at Thr466 increased in aged brains, and JIP1 binding to kinesin-1 decreased, suggesting that APP transport is impaired by aging. We conclude that phosphorylation of KLC1 at Thr466 regulates the velocity of transport of APP by kinesin-1 by modulating its interaction with JIP1b.
在神经元中，淀粉样β蛋白前体（APP）通过与驱动蛋白-1结合进行运输，这一过程由JNK相互作用蛋白1b（JIP1b）介导，它能产生APP顺行运输的增强快速速度（EFV）和高效高频（EHF）。此前，我们发现EFV需要JIP1b C末端区域与驱动蛋白轻链1（KLC1）四肽重复序列之间的常规相互作用，而EHF需要JIP1b中央区域与KLC1卷曲螺旋结构域之间的新型相互作用。我们发现KLC1的可磷酸化苏氨酸466调节与JIP1b的常规相互作用。将苏氨酸466替换为谷氨酸消除了这种相互作用和EFV，但不损害负责EHF的新型相互作用。在老年大脑中，KLC1苏氨酸466的磷酸化增加，且JIP1与驱动蛋白-1的结合减少，这表明衰老会损害APP的运输。我们得出结论，KLC1苏氨酸466的磷酸化通过调节其与JIP1b的相互作用来调节驱动蛋白-1对APP的运输速度。
