同源蛋白質-蛋白質交互作用之研究

Abstract

對新發現的蛋白質而言，其同源序列(sequence homolog)及同源結構(structural homolog)通常能提供研究者關於該蛋白質生物功能(function)、功能區塊(domain)的若干線索。更進一步，我們提出一個新的概念「同源蛋白質-蛋白質交互作用(homologous protein-protein interaction, 簡稱homologous PPI)」，此概念對於了解新被發現的蛋白質交互作用是很有幫助的。在此研究中，我們提出一套合理定義、鑑別homologous PPIs的方法論，並提供了自然界中homologous PPIs確實存在的證據。而在現今PPI資料迅速增加的情況下，研究者迫切地需要能夠快速搜尋並提供合理homologous PPIs的方法，以對未知功能的PPI進行深入的研究。為達成此目的，我們將本研究中發展出的方法論與一個大型PPI資料庫(包含來自576個物種的290,137筆PPIs)結合，建立了一個網路服務工具PPISearrh (http://gemdock.life.nctu.edu.tw/ppisearch/)，使用者可輸入任一提問蛋白質對(query protein pair)，它具有快速搜尋該提問蛋白質對之homologous PPIs (亦稱PPI family)的功能，並已開放給全球研究者使用。 本研究亦提供統計基礎，將homologous PPIs所具有的生物功能及功能區塊用來合理地註解未知性質的蛋白質間交互作用，其觀念與用同源序列(或結構)來了解某個新發現蛋白質相類。本研究中我們提出，homologous PPIs須具備三個條件：是提問蛋白質對中兩個蛋白質的同源序列之配對；已知紀錄在資料庫中；以及足夠顯著的(E-value ≤ 10-40)合成序列相似度(joint sequence similarity)。 在本研究中，我們也初步將homologous PPI的新概念運用於兩個研究課題，第一是跨物種的蛋白質間交互作用之預測(cross-species PPI prediction)，另一個是跨物種間蛋白質交互作用網絡之比對(cross-species network comparison)。目前只有數種模式生物(model organisms)已累積大量的PPI資料，其蛋白質交互作用網絡可被較完整地了解，我們的初步成果顯示，homologous PPI之概念可以對研究上述兩個課題有所助益。

The discovery of sequence and structural homologs to a known protein often provides clues, such as biochemical function and domain, for understanding a newly determined protein. In this thesis, we have proposed a new concept of "homologous protein-protein interaction (PPI)", which is helpful for understanding a newly determined PPI. We proposed evidence of the existence of homologous PPIs, developed a methodology to rapidly identify homologous PPIs, and infer the transferability of interacting domains and functions of a query protein pair. We found that homologous PPIs can be distinguished when homolog pairs were in the annotated database and have significant joint sequence similarity (E-value ≤10-40) with the query protein pair. As an increasing number of reliable PPIs become available and high-throughput experimental methods provide systematic identification of PPIs, there is a growing need for fast and accurate methodologies for discovering homologous PPIs of a PPI. For this demand, we combined the methodology with an annotated PPI database (290,137 PPIs in 576 species) to construct a PPISearch server (http://gemdock.life.nctu.edu.tw/ppisearch/) to supply service for global researchers. In addition, we have utilized the concept of homologous PPIs to cross-species PPI prediction and cross-species network comparison. Currently, large-scale interaction networks are available for only several model organisms. Our preliminary results suggested that the concept of homologous PPI are useful for a systematic transfer of PPI networks between multiple species.