KIF1Bβ- and KIF1A-mediated axonal transport of presynaptic regulator Rab3 occurs in a GTP-dependent manner through DENN/MADD
KIF1Bβ- and KIF1A-mediated axonal transport of presynaptic regulator Rab3 occurs in a GTP-dependent manner through DENN/MADD
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DOI：
10.1038/ncb1785
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发表时间：
2008-11-01
影响因子：
21.3
通讯作者：
Hirokawa, Nobutaka
中科院分区：
文献类型：
--
作者：
Niwa, Shinsuke;Tanaka, Yosuke;Hirokawa, Nobutaka
突触蛋白在细胞体中合成，并通过微管依赖性马达沿轴突向下运输。我们以前报道过，KIF 1B β和KIF 1A马达对于运输突触囊泡前体是必不可少的;然而，调节运输的机制以及货物识别和货物装载和卸载的控制在很大程度上仍然未知。在这里，我们表明DENN/MADD（Rab 3-GEP）是通过与KIF 1B β和KIF 1A的茎域直接相互作用的调节机制的重要组成部分。我们还表明，DENN/MADD优先结合GTP-Rab 3，并作为Rab 3效应。这些分子相互作用是基本的，因为连续的遗传扰动揭示了KIF 1B β和KIF 1A对于DENN/MADD和Rab 3的转运是必不可少的，而DENN/ MADD对于Rab 3的转运是必不可少的。GTP-Rab 3比GDP-Rab 3更有效地转运，这表明Rab 3的核苷酸状态通过与DENN/ MADD的优先相互作用来调节Rab 3携带囊泡的轴突转运。
Synaptic proteins are synthesized in the cell body and transported down the axon by microtubule-dependent motors. We previously reported that KIF1B beta and KIF1A motors are essential for transporting synaptic vesicle precursors; however the mechanisms that regulate transport, as well as cargo recognition and control of cargo loading and unloading remain largely unknown. Here, we show that DENN/MADD (Rab3-GEP) is an essential part of the regulation mechanism through direct interaction with the stalk domain of KIF1B beta and KIF1A. We also show that DENN/MADD binds preferentially to GTP-Rab3 and acts as a Rab3 effector. These molecular interactions are fundamental as sequential genetic perturbations revealed that KIF1B beta and KIF1A are essential for the transport of DENN/MADD and Rab3, whereas DENN/ MADD is essential for the transport of Rab3. GTP-Rab3 was more effectively transported than GDP-Rab3, suggesting that the nucleotide state of Rab3 regulates axonal transport of Rab3-carrying vesicles through preferential interaction with DENN/ MADD.