Clarke Paul R, Zhang Chuanmao
Ninewells Hospital and Medical School, University of Dundee, Scotland.
Symp Soc Exp Biol. 2004(56):193-204.
Using evidence derived primarily from studies using Xenopus egg extracts, a model for the role of Ran in multiple stages during NE assembly can be proposed (Figure 2). Ran is concentrated on chromatin prior to NE assembly and recruits RCC1 that generates Ran-GTP locally. Recruitment of RCC1 to chromatin may be a specialized mechanism to initiate NE assembly following fertilization of the egg, whereas in somatic cells, RCC1 may be present on chromatin throughout mitosis. Ran-GTP recruits vesicles to the surface of chromatin, and promotes vesicle fusion to form the double membrane of the NE. Ran-GTP may recruit membrane vesicles to chromatin through binding to integral membrane proteins through importin-beta. A transient complex would be formed between Ran-GTP, importin-beta and the target protein, which would be released locally to promote assembly of a precursor complex. GTP hydrolysis by Ran would release importin-beta, but may also play a role in vesicle fusion. Ran-GTP also promotes NPC assembly by releasing nucleoporins such as Nup107 from inhibitory complexes with importin-beta. In vertebrate cells undergoing mitosis, the majority of Ran molecules are excluded from the chromosomes and dispersed into the cytoplasm. Relocalization of Ran to chromatin at the end of mitosis may co-ordinate the initiation of NE assembly with disassembly of the mitotic spindle. The function of Ran in this transition is likely to be coupled to changes in the activity of cyclin-dependent protein kinases and other activities that control the progression of the cell cycle. Thus, changes in the localization of Ran and its regulators provide temporal and spatial control of NE assembly at the end of mitosis.
利用主要来自爪蟾卵提取物研究的证据，可以提出一个Ran在核膜组装多个阶段所起作用的模型（图2）。在核膜组装之前，Ran集中在染色质上，并招募能在局部产生Ran-GTP的RCC1。RCC1募集到染色质上可能是卵子受精后启动核膜组装的一种特殊机制，而在体细胞中，RCC1在整个有丝分裂过程中可能都存在于染色质上。Ran-GTP将囊泡募集到染色质表面，并促进囊泡融合以形成核膜的双层膜。Ran-GTP可能通过与整合膜蛋白结合，经importin-β将膜囊泡募集到染色质上。Ran-GTP、importin-β和靶蛋白之间会形成一个瞬时复合物，该复合物会在局部释放以促进前体复合物的组装。Ran催化GTP水解会释放importin-β，但也可能在囊泡融合中起作用。Ran-GTP还通过从与importin-β的抑制复合物中释放核孔蛋白如Nup107来促进核孔复合体的组装。在进行有丝分裂的脊椎动物细胞中，大多数Ran分子被排除在染色体之外并分散到细胞质中。有丝分裂末期Ran重新定位到染色质上可能将核膜组装的起始与有丝分裂纺锤体的解体协调起来。Ran在这一转变过程中的功能可能与细胞周期蛋白依赖性蛋白激酶活性的变化以及控制细胞周期进程的其他活动相关联。因此，Ran及其调节因子定位的变化在有丝分裂末期对核膜组装提供了时间和空间上的控制。
