Protein phase separation provides long-term memory of transient spatial stimuli
Protein phase separation provides long-term memory of transient spatial stimuli
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DOI：
10.1101/283804
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发表时间：
2018-03
期刊：
影响因子：
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通讯作者：
E. Dine;Agnieszka A Gil;Giselle Uribe;C. Brangwynne;Jared E. Toettcher
中科院分区：
文献类型：
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作者：
E. Dine;Agnieszka A Gil;Giselle Uribe;C. Brangwynne;Jared E. Toettcher
从发育中的胚胎中P颗粒和PAR蛋白的不对称分布到迁移细胞中的局部受体低聚物，蛋白质/RNA簇在空间调控的生物过程中经常出现。这种共存现象表明，蛋白质簇可能具有使其成为空间调节有用底物的内在特性。在这里，我们证明了蛋白质液滴表现出一种强大的空间记忆形式，在去除液滴形成抑制剂后很长一段时间内保持其空间模式。尽管这种持久性，液滴可以是高度动态的，不断地与扩散相交换单体。我们在三种情况下研究了生物物理空间记忆的原理：相分离的计算模型；一种新型光遗传系统，光可以驱动液体状蛋白滴的快速、局部解离；以及来自受体酪氨酸激酶簇的膜定位信号转导。我们的研究结果表明，许多细胞和发育过程背后的持续极化可能通过一个简单的生物物理过程产生，而不需要任何额外的生化正负反馈循环。我们介绍了PixELLs，一个用于蛋白质液滴分解的光遗传系统。模型和实验证明了局部液滴分离的长期记忆。液滴在细胞核、细胞质和细胞膜上“记住”空间刺激。fgfr - optodrops将短暂的局部输入转化为持续的细胞骨架反应。
Protein/RNA clusters arise frequently in spatially-regulated biological processes, from the asymmetric distribution of P granules and PAR proteins in developing embryos to localized receptor oligomers in migratory cells. This co-occurrence suggests that protein clusters might possess intrinsic properties that make them a useful substrate for spatial regulation. Here, we demonstrate that protein droplets show a robust form of spatial memory, maintaining the spatial pattern of an inhibitor of droplet formation long after it has been removed. Despite this persistence, droplets can be highly dynamic, continuously exchanging monomers with the diffuse phase. We investigate the principles of biophysical spatial memory in three contexts: a computational model of phase separation; a novel optogenetic system where light can drive rapid, localized dissociation of liquid-like protein droplets; and membrane-localized signal transduction from clusters of receptor tyrosine kinases. Our results suggest that the persistent polarization underlying many cellular and developmental processes could arise through a simple biophysical process, without any additional requirement for biochemical positive and negative feedback loops. Highlights We introduce PixELLs, an optogenetic system for protein droplet disassembly. Modeling and experiments demonstrate long-term memory of local droplet dissociation. Droplets ‘remember’ spatial stimuli in nuclei, the cytosol and on cell membranes. FGFR-optoDroplets convert transient local inputs to persistent cytoskeletal responses.