Membrane identity and GTPase cascades regulated by toggle and cut-out switches
Membrane identity and GTPase cascades regulated by toggle and cut-out switches
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DOI：
10.1038/msb.2008.45
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发表时间：
2008-07-01
影响因子：
9.9
通讯作者：
Deutsch, Andreas
中科院分区：
文献类型：
--
作者：
Del Conte-Zerial, Perla;Brusch, Lutz;Deutsch, Andreas
关键的细胞功能和发育过程依赖于GTP酶的级联。Rab家族的GTP酶为细胞内隔室的产生、维持和运输提供了一个分子ID编码。在这里，我们讨论了内吞作用的分子设计原则，重点是早期内吞体内到晚期内吞体内的转换，这需要Rab5被Rab7取代。我们将这一过程建模为相互作用的Rab GTP酶的级联功能模块。我们证明了模块间的相互作用与细胞周期所描述的触发开关有相似之处。然而，Rab5到Rab7的转换更多地是基于一种新表征的类似于电气安全断路器的“切断开关”。这两种设计都需要在连接到大量细胞质蛋白质池时自激活环的协同性。活细胞成像和内小体跟踪为货物运输和内小体特性沿降解途径的转换中的切断开关提供了实验支持。我们认为，通过协调模块的性能和活动的进展，断路开关设计可以为广泛的生物过程的调节级联中模块的整合奠定基础。
Key cellular functions and developmental processes rely on cascades of GTPases. GTPases of the Rab family provide a molecular ID code to the generation, maintenance and transport of intracellular compartments. Here, we addressed the molecular design principles of endocytosis by focusing on the conversion of early endosomes into late endosomes, which entails replacement of Rab5 by Rab7. We modelled this process as a cascade of functional modules of interacting Rab GTPases. We demonstrate that intermodule interactions share similarities with the toggle switch described for the cell cycle. However, Rab5-to-Rab7 conversion is rather based on a newly characterized 'cut-out switch' analogous to an electrical safety-breaker. Both designs require cooperativity of autoactivation loops when coupled to a large pool of cytoplasmic proteins. Live cell imaging and endosome tracking provide experimental support to the cut-out switch in cargo progression and conversion of endosome identity along the degradative pathway. We propose that, by reconciling module performance with progression of activity, the cut-out switch design could underlie the integration of modules in regulatory cascades from a broad range of biological processes.