RoL: FELS: EAGER: Design Rules for Multidomain Proteins Across the Tree of Life

该项目旨在发现细胞生物学如何塑造多结构域蛋白的设计规则。多结构域蛋白是编码结构或功能模块的序列片段的嵌合体，称为结构域。多结构域蛋白质的模块化特性是其功能不可或缺的一部分，因为不同的组成结构域起着不同的功能作用。例如，在信号蛋白中，一些结构域负责识别环境信号，另一些负责传递环境信号。这些模块化蛋白质允许细胞通过细胞间信号传导、细胞粘附和细胞迁移与外界相互作用。在人类健康中，多结构域家族是细胞凋亡、先天免疫、炎症反应和组织修复的基础。在自然界中观察到的多领域体系结构代表了可能的领域组合的一小部分。这些结构域组合是突变过程的产物，产生新的序列镶嵌和促进或阻止它们保留的选择力。在特定物种中，突变和选择都依赖于基因组组织、DNA复制、转录和修复机制以及细胞与环境的相互作用。不同物种之间的多域结构差异很大，基因组和细胞特性也是如此。该项目利用这种比较框架来研究细胞生物学如何塑造多域进化过程。这项研究有可能通过确定多域设计规则来改变我们对蛋白质进化的理解，这些规则可能为连接进化和功能的预测模型提供基础，并为人类健康和蛋白质工程提供具体应用。该项目通过开发和分发可能有助于国家科学资源的计算工具来推进研究基础设施。该项目还通过为卡耐基梅隆大学计算生物学本科项目的女性提供研究经验，有助于建立一支广泛包容的科学工作队伍。本项目采用三管齐下的方法来研究多结构域蛋白的通用和谱系特异性设计规则。首先，将开发计算工具，通过将多域家族建模为与相关基因和物种共同进化的一组域，来推断域、基因和物种水平上的进化。每个实体都由一个进化树表示。进化事件的历史是通过域、基因和物种树的拓扑比较来推断的。结合来自三个生物组织层次的信息，揭示了相对于基因、基因组和生物体进化中的事件何时发生域事件，为研究域结构的变化如何与基因组和细胞特性的变化相关联提供了所需的信息。其次，这些方法被应用于重建脊椎动物和蛋白质细菌基因组的多域进化，揭示了共享和谱系特异性的进化模式。第三，将这些进化模式与脊椎动物和变形细菌细胞中基因组组织和细胞机制的差异进行比较，将有助于推断跨生命之树的多域进化设计规则。结果数据和计算工具将在http://www.cs.cmu.edu/??durand/Lab/multidomain.html.This上提供，该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

This project seeks to discover how the biology of the cell shapes the design rules of multidomain proteins. Multidomain proteins are mosaics of sequence fragments that encode structural or functional modules, called domains. The modular nature of a multidomain protein is integral to its function because different constituent domains play different functional roles. For example, in signaling proteins, some domains are responsible for the recognition and others for the transmission of an environmental signal. These modular proteins allow cells to interact with their world, via cell-cell signaling, cellular adhesion, and cellular migration. In human health, multidomain families are fundamental to apoptosis, innate immunity, inflammation response, and tissue repair. The multidomain architectures that are observed in nature represent a tiny fraction of possible domain combinations. These domain combinations are the product of the mutational processes that give rise to new sequence mosaics and the selective forces that promote or discourage their retention. In a given species, mutation and selection are both dependent on genome organization, mechanisms of DNA replication, transcription and repair, and the interaction of the cell with its environment. Multidomain architectures vary substantially across species, as do genomic and cellular properties. This project exploits this comparative framework to investigate how the biology of the cell shapes the processes of multidomain evolution. This research has the potential to transform our understanding of protein evolution by identifying multidomain design rules that may provide a foundation for predictive models linking evolution and function, with concrete applications for human health and protein engineering. This project advances research infrastructure through the development and distribution of computational tools that may contribute to national scientific resources. This project also contributes to building a broadly inclusive scientific work force through research experiences for women in Carnegie Mellon's undergraduate program in computational biology.This project uses a three-pronged approach to investigate the universal and lineage-specific design rules of multidomain proteins. First, computational tools will be developed to infer evolution on the domain, gene, and species levels, by modeling a multidomain family as a set of domains that are co-evolving with the associated genes and species. Each entity is represented by an evolutionary tree. The history of evolutionary events is inferred using topological comparison of the domain, gene, and species trees. Combining information from three levels of biological organization reveals when domain events occurred relative to events in gene, genome, and organismal evolution, providing the information required to investigate how changes in domain architecture correlate with changes in genomic and cellular properties. Second, these methods are applied to reconstruct multidomain evolution in vertebrate and proteobacterial genomes, revealing shared and lineage-specific evolutionary patterns. Third, comparison of these evolutionary patterns with differences in genome organization and cellular machinery in vertebrate and proteobacterial cells will support the inference of design rules for multidomain evolution across the tree of life. The resulting data and computational tools will be available at http://www.cs.cmu.edu/??durand/Lab/multidomain.html.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.