Molecular Evolution of Cellular Condensates

活细胞是由许多称为蛋白质的分子机器组成的。许多蛋白质采用专用于它们进行的细胞活动的结构，正如预期的那样，这些结构往往在长时间的进化中保持不变。最近，生物学家开始意识到，一些蛋白质采用了更灵活的构象，使它们能够通过与类似蛋白质聚集来发挥作用。这个项目试图了解这种组织细胞和调节复杂功能的方式如何影响组成这种簇的蛋白质如何通过进化改变的规则。结合这个项目的研究目标，研究人员将开发一个使用分子动画的教学课程，并将这些材料分发给细胞生物学教师，以帮助培训下一代研究人员。传统上认为，所有的细胞器都被限制在一个膜内。然而，近年来，无膜细胞器或凝集物是一种新的组织细胞的方法。凝析油的形成和功能受相互作用的调节，这种相互作用比更普遍研究的蛋白质更动态和更不稳定，影响凝析油成分的演变。该项目系统地分析了模式生物秀丽线虫的冷凝物成分，以阐明冷凝物成员的分子语法和塑造冷凝物进化的力量。然后，通过突变和交换保守结构域并测试这些变化的功能影响来验证通过系统发育分析发现的进化模式和规则。除了深入了解凝聚体的功能和进化，这项工作还为同源搜索算法的未来改进绘制了蓝图，从而改进了基因注释、序列比对和同源同源鉴定。该项目的实验工作得到了关于凝析油的教学课程的创建的补充，其中包括适合于表现凝析油形成和功能以及凝析油背后的动态相互作用的专用动画。将这些材料分发给细胞生物学教师将有助于培训下一代研究人员。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Living cells are composed of numerous molecular machines called proteins. Many proteins adopt structures dedicated to the cellular activities they carry out, and, as expected, these structures tend to persist over long evolutionary times. Recently, biologists started to appreciate that some proteins adopt much more flexible conformations that allow them to function by clustering with similar proteins. This project seeks to understand how this way of organizing the cell and regulating complex functions affects the rules governing how proteins that constitute such clusters change through evolution. In conjunction with the research goals of this project, the investigator will be developing a teaching curriculum using molecular animation and distributing these materials to cell biology instructors to help train the next generation of researchers. It has been traditionally believed that all cellular organelles are confined within a membrane. However, in recent years, membrane-less organelles, or condensates, are a newly appreciated way to organize the cell. The formation and functions of condensates are regulated by interactions more dynamic and labile than that of more commonly studied proteins, impacting how condensate constituents evolve. This project systematically analyzes condensate constituents in the model organism Caenorhabditis elegans to shed light on the molecular grammar of condensate members and on the forces shaping condensate evolution. The evolutionary patterns and rules uncovered by the phylogenetic analysis are then validated by mutating and swapping conserved domains and testing the functional impact of these changes. Beyond insight into the functions and evolution of condensates, this work charts a blueprint for future refinements of homology search algorithms resulting in improved gene annotations, sequence alignments and ortholog identification. The experimental work on this project is complemented by the creation of a teaching curriculum about condensates, including dedicated animations suited to represent dynamic interactions underlying the formation and functions and condensates. Distributing these materials to cell biology instructors will help train the next generation of researchers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.