Construction and characterization of E3-mediated regulatory networks for cellular functions and human diseases

Abstract

Ubiquitination is a post-translational modification process of attaching an ubiquitin molecule to other proteins and most proteins marked with ubiquitin are degraded by proteasome. Ubiquitination is responsible for controlling the turnover of ~80% of cellular proteins, thereby affecting a variety of cellular processes and human diseases. A family of enzymes, called E3 ligase (E3), is of particular importance in the ubiquitination process by recognizing and targeting specific substrate proteins. A variety of E3s are found with varying substrate specificities, which indicates that the degradation process is specifically controlled by E3s. Thus, a comprehensive knowledge about E3s and their specific substrates is necessary for further researches for ubiquitination. However, the current findings of E3-substrate relationships are scattered over a number of resources, making it difficult to analyze functional implications of E3-mediated regulations on diverse cellular processes and pathological phenotypes in a systemic or systematic manner. In this thesis, we integrated this scattered data into a comprehensive E3-substrate network and constructed E3-mediated regulatory networks for cellular functions and human diseases by analyzing functional and pathological characteristics of individual E3-specific substrate groups. Firstly, we extracted known E3-substrate relationships from MEDLINE abstracts and UniProt database by using a text-mining method as well as from high-throughput experiments data and public ubiquitination databases. This integrative collection scheme substantially enhanced the contents of E3-substrate network, corresponding to a 10-fold increase in the number of E3-substrate relationships compared with previous ubiquitination databases. On the basis of the comprehensive E3-substrate network, we constructed E3Net system, which provides a framework to analyze various cellular functions associated with individual E3-specific substrate groups. Through the a...