ProteinArchitect: Protein Evolution above the Sequence Level

BackgroundWhile many authors have discussed models and tools for studying protein evolution at the sequence level, molecular function is usually mediated by complex, higher order features such as independently folding domains and linear motifs that are based on or embedded in a particular arrangment of features such as secondary structure elements, transmembrane domains and regions with intrinsic disorder. This ‘protein architecture’ can, in its most simplistic representation, be visualized as domain organization cartoons that can be used to compare proteins in terms of the order of their mostly globular domains.
MethodologyHere, we describe a visual approach and a webserver for protein comparison that extend the domain organization cartoon concept. By developing an information-rich, compact visualization of different protein features above the sequence level, potentially related proteins can be compared at the level of propensities for secondary structure, transmembrane domains and intrinsic disorder, in addition to PFAM domains. A public Web server is available at www.proteinarchitect.net, while the code is provided at protarchitect.sourceforge.net.
Conclusions/SignificanceDue to recent advances in sequencing technologies we are now flooded with millions of predicted proteins that await comparative analysis. In many cases, mature tools focused on revealing hits with considerable global or local similarity to well-characterized proteins will not be able to lead us to testable hypotheses about a protein's function, or the function of a particular region. The visual comparison of different types of protein features with ProteinArchitect will be useful when assessing the relevance of similarity search hits, to discover subgroups in protein families and superfamilies, and to understand protein regions with conserved features outside globular regions. Therefore, this approach is likely to help researchers to develop testable hypotheses about a protein's function even if is somewhat distant from the more characterized proteins, by facilitating the discovery of features that are conserved above the sequence level for comparison and further experimental investigation.

研究背景：尽管诸多学者已针对序列层面的蛋白质进化研究开发了相关模型与工具，但蛋白质的分子功能通常由复杂的高阶特征所介导，例如独立折叠结构域与线性基序；这些特征基于或嵌入于特定的特征排布之中，包括二级结构元件、跨膜结构域以及内在无序区域。这种“蛋白质架构(protein architecture)”以最简化的形式可被可视化作结构域组织示意图，用于基于多数球状结构域的排列顺序对蛋白质进行比对。
研究方法：本研究提出一种拓展了结构域组织示意图理念的可视化方法与蛋白质比对网页服务器。通过构建序列层面之上的多样化蛋白质特征的信息丰富且紧凑的可视化方案，除可比对PFAM数据库(PFAM)结构域外，还可基于二级结构、跨膜结构域与内在无序区域的倾向性对潜在同源蛋白质进行比对。该工具的公开网页服务器部署于www.proteinarchitect.net，源代码则公开于protarchitect.sourceforge.net。
结论与意义：得益于测序技术的新近进展，如今已有数以百万计的预测蛋白质亟待开展比对分析。在诸多场景中，专注于寻找与经过充分注释的蛋白质存在显著全局或局部相似性比对命中的成熟工具，往往无法为我们提供可验证的蛋白质功能或特定区域功能的研究假说。借助蛋白质架构比对工具(ProteinArchitect)对不同类型的蛋白质特征进行可视化比对，可用于评估相似性搜索命中结果的相关性、发现蛋白质家族与超家族中的亚类，以及解析球状区域之外携带保守特征的蛋白质区域。因此，即便待研究蛋白质与已充分注释的同源蛋白质亲缘关系较远，该方法也可通过助力发现序列层面之上的保守特征以用于比对与后续实验研究，帮助研究者构建可验证的蛋白质功能研究假说。