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

本研究从分子细胞生物学、分子遗传学、生物物理学和结构生物学等方面对细胞内转运的机制进行了研究。1）对驱动蛋白超家族蛋白的所有基因进行了鉴定，2）KIF 1B β转运突触囊泡前体，是神经元功能和存活的基础，是人类遗传性神经病的责任基因。KIF 2A解聚微管并抑制轴突分支的不必要的延伸，因此对脑发育至关重要。4）KIF 3将N钙粘蛋白和β-连环蛋白从高尔基体转运到质膜，并通过抑制β-连环蛋白转移到细胞核及其作为细胞增殖的转录因子的功能来抑制肿瘤发生。5）KIF 3在早期胚胎腹侧结的纤毛中转运蛋白复合物。纤毛通过轴向后倾斜的旋转产生胚外液的结节流。节点流 ...更多信息 依赖于FGF信号向左输送从结细胞释放的富含脂质的结囊泡包裹，并确定左右不对称性。因此，KIF 3是重要的身体规划的基础。6）KIF 5通过KIF 5尾和GRIP 1-GluR 2之间的相互作用在树突中转运AMPA型谷氨酸受体。7）KIF 5还在树突中转运与RNA相关的大蛋白复合物的mRNA。8）KIF 17通过KI 17尾和支架蛋白复合物之间的相互作用在树突中转运NMDA型谷氨酸受体，这种转运被证明是9）KIFC 3将含有Anexin XIIIb的囊泡转运到上皮细胞的顶膜，并在高尔基体的定位和完整性中起作用。10）作为轴突与树突的差异转运机制，我们确定了两种机制。一种是通过马达结构域识别轴突起始段微管的差异，另一种是通过货物与尾结构域的结合来控制。11）我们揭示了马达蛋白可以通过偏置布朗运动作为单体沿着沿着向前移动，并解决了ATP水解过程中KIF 1A马达结构域5种不同状态的原子结构，因此，构象变化如何发生在马达域。12）我们解决了ADP和ATP样状态的KIF 2的原子结构，并阐明了KIF 2如何解聚微管。少

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