Article abstract
Nature Cell Biology 10, 1269 - 1279 (2008)
Published online: 12 October 2008 | doi:10.1038/ncb1785
KIF1B
- and KIF1A-mediated axonal transport of presynaptic regulator Rab3 occurs in a GTP-dependent manner through DENN/MADD
Shinsuke Niwa1, Yosuke Tanaka1 & Nobutaka Hirokawa1
Abstract
Synaptic proteins are synthesized in the cell body and transported down the axon by microtubule-dependent motors. We previously reported that KIF1B
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 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 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.
- Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Correspondence to: Nobutaka Hirokawa1 e-mail: hirokawa@m.u-tokyo.ac.jp
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