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

我们对细胞内转运机制的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进行了阐述。1)对Kinesin超家族蛋白的所有基因进行了鉴定。2)KIF1Bβ转运突触小泡前体和神经元功能和生存的基础，它是人类遗传性神经疾病的负责基因。3)KIF2A解聚微管，抑制轴突分支的不必要延伸，从而对脑连接非常重要。4)KIF3将Ncadherin和β-catenin从高尔基体转运到质膜，通过抑制β-catenins进入细胞核而抑制肿瘤的发生，并作为细胞增殖的转录因子。5)KIF3转运蛋白质复合体在胚胎早期腹侧节点的纤毛中。纤毛通过轴向后倾斜的旋转产生胚外液体向左的结节流动。节流…更多的是依赖于成纤维细胞生长因子信号将结节细胞释放的富含脂质的结节泡囊向左输送，并决定左右不对称。6)KIF5通过KIF5尾巴和GRIP1-GluR2.7之间的相互作用在树突中运输AMPA型谷氨酸受体。2.7)KIF5还运输mRNAs和树突中与RNA相关的大型蛋白质复合体。8)KIF17通过KI17尾巴和支架蛋白复合体之间的相互作用在树突中运输NMDA型谷氨酸受体，这种运输被证明对高级大脑功能，如工作和特殊记忆是重要的。9)KIFC3运输含有Anexin XIIIB的囊泡到上皮细胞的顶膜，并在Golgi器的定位和完整性中发挥作用。10)作为区别运输到轴突和树突的机制，我们发现了两种机制。11)我们揭示了马达蛋白可以通过偏向的布朗运动作为单体沿着微管进行运动，并解决了KIF1A马达结构域在ATP水解过程中5种不同状态的原子结构，从而在马达结构域中发生了构象变化。12)我们求解了KIF2的ADP和ATP样态的原子结构，阐明了KIF2是如何解聚微管的。较少

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