Molecular mechanism of Intracellular Transport: Approaches from molecular Cell Biology, Structural Biology, and Molecular Genetics.

细胞内转运的分子机制：分子细胞生物学、结构生物学和分子遗传学的方法。

基本信息

批准号：
13CE2004
负责人：
HIROKAWA Nobutaka
金额：
$ 1255.04万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for COE Research
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2005
项目状态：
已结题

项目摘要

Our research concerning the mechanism of intracellular transport elucidated followings using molecular cell biology, molecular genetics, biophysics and structural biology.1) Identification of all genes of kinesin superfamily proteins, KIFs in mammals such as human and mouse.2) KIF1B beta transport synaptic vesicle precursor and fundamental for neuronal function and survival and it is a responsible gene of a human hereditary neuropathy.3) KIF2A depolymerizes microtubules and suppress unnecessary extension of axonal branches thus important for brain wiring.4) KIF3 transports Ncadherin and beta-catenin from Golgi to plasma membrane and suppresses tumorigenesis by suppressing beta-catenins transfer into the nucleus and its function as a transcriptional factor for cell proliferation.5) KIF3 transports protein complexes in the cilia at the ventral node in early embryo. The cilia generate leftward nodal flow of extraembryonic fluid by rotation whose axis is tilted posteriorly. The nodal flow … More convey lipid-enriched nodal vesicular parcels released from node cells dependent on FGF signaling toward left and determine left-right asymmetry. Thus KIF3 is fundamental for important body planning.6) KIF5 transport AMPA type glutamate receptors in dendrites through the interaction between KIF5 tail and GRIP1 - GluR2.7) KIF5 also transport mRNAs with a large protein complexes related to RNAs in dendrites.8) KIF17 transport NMDA type glutamate receptors in dendrites through interaction between KI17tail and scaffolding protein complexes and this transport is shown to be important for higher brain function such as working and special memories.9) KIFC3 transports vesicles containing Anexin XIIIb to the apical membrane of epitherial cells, and plays a role in localization and integrity of the Golgi apparatus.10) As mechanisms for differential transport to axon vs dendrites we identified two mechanism. One is by the recognition of the difference of microtubules in the axon initial segment by motor domain and other is by control via binding of cargoes to the tail domain.11) We revealed that motor protein can move processively along microtubules as monomer by biased Brownian movement and also solved atomic structure of KIF1A motor domain of 5 different states during ATP hydrolysis, thus how conformational changes occur in the motor domain.12) We solved atomic structures of ADP and ATP like states of KIF2 and elucidated how KIF2 depolymerizes microtubules. Less

我们利用分子细胞生物学、分子遗传学、生物物理学和结构生物学对细胞内运输机制进行的研究阐明了以下内容。1) 鉴定人类和小鼠等哺乳动物中驱动蛋白超家族蛋白、KIF 的所有基因。2) KIF1B β 运输突触小泡神经功能和生存的前体和基础，它是人类遗传性神经病的一个负责基因。3) KIF2A 解聚微管并抑制轴突分支不必要的延伸，因此对大脑布线很重要。4) KIF3 将 Ncadherin 和 β-catenin 从高尔基体转运到质膜，并通过抑制 β-catenin 转移到细胞核及其作为细胞增殖转录因子的功能来抑制肿瘤发生。5 ) KIF3 在早期胚胎腹侧节点的纤毛中运输蛋白质复合物。纤毛通过旋转产生向左的胚胎外液节点流。节点的轴向后倾斜。流…更多依赖 FGF 信号传递从节点细胞释放的富含脂质的节点囊泡包裹，并确定左右不对称性，因此 KIF3 对于重要的身体规划至关重要。6) KIF5 通过之间的相互作用在树突中转运 AMPA 型谷氨酸受体。 KIF5 尾巴和 GRIP1 - GluR2.7) KIF5 还转运具有与树突中 RNA 相关的大蛋白复合物的 mRNA。8) KIF17 转运树突中的 NMDA 型谷氨酸受体通过 KI17tail 和支架蛋白复合物之间的相互作用，并且这种运输被证明对于高级脑功能（例如工作和特殊记忆）很重要。 9) KIFC3 将含有 Anexin XIIIb 的囊泡运输到上皮细胞的顶膜，并且在高尔基体的定位和完整性中发挥着作用。10）作为轴突与树突的差异运输机制，我们确定了两种机制。一种是通过运动结构域识别轴突初始段中微管的差异，另一种是通过将货物与尾部结构域结合来控制。11）我们揭示了运动蛋白可以通过偏向布朗运动作为单体沿着微管进行过程移动，并且还解决了 ATP 水解过程中 5 种不同状态的 KIF1A 运动结构域的原子结构，从而解决了运动结构域中如何发生构象变化。12）我们解决了 ADP 和 ATP 的原子结构，类似于 KIF2 的状态和Less 阐明了 KIF2 如何解聚微管。