Department of Biological Sciences, University of Cyprus, University Avenue 1, 1678, Nicosia, Cyprus.
Cell Mol Life Sci. 2013 Jan;70(2):335-56. doi: 10.1007/s00018-012-1108-0. Epub 2012 Sep 4.
KIF1Bβ is a kinesin-like, microtubule-based molecular motor protein involved in anterograde axonal vesicular transport in vertebrate and invertebrate neurons. Certain KIF1Bβ isoforms have been implicated in different forms of human neurodegenerative disease, with characterization of their functional integration and regulation in the context of synaptic signaling still ongoing. Here, we characterize human KIF1Bβ (isoform NM015074), whose expression we show to be developmentally regulated and elevated in cortical areas of the CNS (including the motor cortex), in the hippocampus, and in spinal motor neurons. KIF1Bβ localizes to the cell body, axon, and dendrites, overlapping with synaptic-vesicle and postsynaptic-density structures. Correspondingly, in purified cortical synaptoneurosomes, KIF1Bβ is enriched in both pre- and postsynaptic structures, forming detergent-resistant complexes. Interestingly, KIF1Bβ forms RNA-protein complexes, containing the dendritically localized Arc and Calmodulin mRNAs, proteins previously shown to be part of RNA transport granules such as Purα, FMRP and FXR2P, and motor protein KIF3A, as well as Calmodulin. The interaction between KIF1Bβ and Calmodulin is Ca(+2)-dependent and takes place through a domain mapped at the carboxy-terminal tail of the motor. Live imaging of cortical neurons reveals active movement by KIF1Bβ at dendritic processes, suggesting that it mediates the transport of dendritically localized mRNAs. Finally, we show that synaptic recruitment of KIF1Bβ is activity-dependent and increased by stimulation of metabotropic or ionotropic glutamate receptors. The activity-dependent synaptic recruitment of KIF1Bβ, its interaction with Ca(2+) sensor Calmodulin, and its new role as a dendritic motor of ribonucleoprotein complexes provide a novel basis for understanding the concerted co-ordination of motor protein mobilization and synaptic signaling pathways.
KIF1Bβ 是一种类驱动蛋白、微管基底的分子马达蛋白，参与脊椎动物和无脊椎动物神经元的顺行轴突囊泡运输。某些 KIF1Bβ 同工型与不同形式的人类神经退行性疾病有关，但其在突触信号背景下的功能整合和调节特征仍在继续研究中。在这里，我们描述了人类 KIF1Bβ（NM015074 同工型），我们发现其表达受到发育调控，并在中枢神经系统（包括运动皮层）的皮质区、海马体和脊髓运动神经元中升高。KIF1Bβ 定位于细胞体、轴突和树突，与突触囊泡和突触后密度结构重叠。相应地，在纯化的皮质突触小体中，KIF1Bβ富含突触前和突触后结构，形成去污剂抗性复合物。有趣的是，KIF1Bβ 形成 RNA-蛋白复合物，包含定位于树突的 Arc 和钙调蛋白 mRNA，这些蛋白质先前被证明是 RNA 运输颗粒（如 Purα、FMRP 和 FXR2P）和运动蛋白 KIF3A 的一部分，以及钙调蛋白。KIF1Bβ 和钙调蛋白之间的相互作用是 Ca(+2)依赖性的，发生在马达羧基末端尾部映射的结构域中。皮质神经元的实时成像显示 KIF1Bβ 在树突过程中的活跃运动，表明它介导了定位于树突的 mRNA 的运输。最后，我们发现 KIF1Bβ 的突触募集是活动依赖性的，并且通过刺激代谢型或离子型谷氨酸受体而增加。KIF1Bβ 的活动依赖性突触募集、其与 Ca(2+) 传感器钙调蛋白的相互作用以及作为核糖体蛋白复合物的树突运动蛋白的新作用，为理解运动蛋白动员和突触信号通路的协同协调提供了新的基础。
