以蛋白質-蛋白質交互作用家族為基礎建立模板導向之同源模組

Abstract

在相同時間和空間尺度下，分子間精確地聚集且協同作用對於生物程序是不可或缺的，例如細胞週期和轉錄作用。模組 (module) 是指一群具有高度連結並執行特定生物功能的蛋白質所組成。就如同同源蛋白質 (homologous protein) 和同源蛋白質-蛋白質交互作用 (homologous protein-protein interaction) 的概念，當一群模組來自一個共同的祖先並且在不同物種中都執行相似的生物功能時，則這些模組被認為是同源模組 (homologous module)。以同源蛋白質-蛋白質交互作用家族為基礎，我們提出一個新概念：「模組家族 (module family)」。模組家族包含一群同源模組，而同源模組是由一群同源蛋白質-蛋白質交互作用家族所構成。從多物種的基因組 (genome) 來推論同源模組可提供一個契機去了解模組的演化和蛋白質交互作用體 (protein interactome)。 在本研究中，透過推論模板導向的方法，將模組家族的概念驗證在MIPS CORUM 資料庫所收集的模組模版 (module template)上。首先，透過同源蛋白質-蛋白質交互作用家族，從1,679個物種定義出同源模組候選者。隨後，當同源模組候選者具備三個條件：第一，蛋白質相似性 (E-values ≤ 10-10)；第二，蛋白質-蛋白質交互作用相似性 (joint E-values ≤ 10-40)；第三，拓撲相似性 (蛋白質-蛋白質交互作用對齊比例 ≥ 0.3和蛋白質對齊比例 ≥ 0.5)，則此模組被認為與它的模組模板相似並稱為模板導向之同源模組 (template-based homologous module)。我們驗證模板導向之同源模組的特性，結果指出其蛋白質間具有高度連結性，以及在Gene Ontology的註解上傾向執行相似的生物功能。 進一步分析模板導向之同源模組的組成特性，我們發現模組家族中的核心組成(core component) 往往是生物體生存所需的必需蛋白質，核心組成乃指跨多物種及物種分群 (division group) 的同源蛋白質-蛋白質交互作用家族，亦即具有高分的蛋白質-蛋白質交互作用演化程度 ( protein-protein interaction evolution score)。 實驗結果指出模組家族中的核心組成在調控模組的生物功能上扮演重要的角色。綜合以上所述，顯示來自模板導向之同源模組的蛋白質-蛋白質交互作用演化程度可以反映出模組家族之必需蛋白質。我們相信同源模組對於了解生命的基本要素有所助益。

Precise assembling and cooperation between molecules in time and space scale are essential for biological processes, such as cell cycle and transcription. A module is a group of proteins that are highly connected and perform a certain kind of biological functions. The modules, which often share a common ancestor and perform similar biological functions across species, can be considered homologous modules, just as homologous proteins and homologous protein-protein interactions (PPIs). Based on PPI families, we proposed a new concept “module family”, which comprises a group of homologous modules consisting of a group of homologous PPIs across species. To infer homologous modules from multiple genomes provides an opportunity to understand the module evolution and protein interactome. In this study, we verified the concept through inferring template-based homologous modules from module templates provided by MIPS CORUM database. First, we identified candidates of homologous modules from 1,679 species through PPI families. Subsequently, the identified candidates were regarded as template-based homologous modules, constituting module families, if the modules are similar to their module template with (i) protein similarity (E-values ≤ 10-10), (ii) PPI similarity (joint E-values ≤ 10-40), and (iii) topology similarity (PPI aligned ratio ≥ 0.3 and protein aligned ratio ≥ 0.5). We examined the properties of the template-based homologous modules, and the results showed that the template-based homologous modules often contain the high connectivity and its protein members perform similar biological functions based on Gene Ontology terms. We further analyzed the component properties of the template-based homologous modules. We found that the core components, which are the consensus of PPI families across multiple species and division groups (i.e. high PPI evolution score), of the module families are often essential proteins for the survival of an organism. Our results showed that the core components of module families play an important role to regulate biological functions of module. In conclusion, the experimental results reveal that the PPI evolution score derived from template-based homologous modules could reflect essential proteins of a module family. We believe that homologous modules are useful to understand essential elements of a life.