Discovery of glycosyltransferase OGT regulatory networks based on protein-protein interactions and glycosylation site specificities in human liver cancer
| Autor: | Hui-Ju Kao, 高慧茹 |
|---|---|
| Rok vydání: | 2019 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 107 While occurring enzymatically in biological systems, O-linked glycosylation affects protein folding, localization and trafficking, protein solubility, antigenicity, biological activity, as well as cell-cell interactions on membrane proteins. Catalytic enzymes involve glycotransferases, sugar-transferring enzymes and glycosidases which trim specific monosaccharides (sugars) from precursors to form intermediate structures. Due to the difficulty of experimental identification, a web server OGTSite has been proposed to computationally identify O-GlcNAcylation sites. In addition, due to the very important roles of glycotransferases by recognizing specific protein substrate and catalyzing the attachment of glycan to the target protein, the investigation of the glycotransferases regulations and glycosylated substrate proteins is emerging as a hot topic. However, there is a lack of methods proposed and tools designed to explore the regulatory networks of glycotransferases for glycosylated proteins. Thus, we are motivated to develop a new method to explore the regulatory networks of glycotransferases for glycosylated proteins. In this dissertation, we focus on the integration of glycosylation site databases, identification of glycotransferase-specific glycosylation sites, and systematic discovery of glycotransferase-substrate network in protein glycosylation. We incorporate computational model with protein associations (protein-protein interactions, functional associations, and gene expression profile of OGT, substrates and OGT-interacting proteins in liver hepatocellular carcinoma (LIHC)) to identify the catalytic glycotransferases for each glycoprotein with experimental glycosylated sites. With the highly predictive performance of glycosylation sites, a better understanding of relationships between glycotransferases and substrates will be facilitated and engineered to analyze the therapeutic usefulness. The identified glycotransferase-substrate interactions are used to comprehensively construct the intracellular glycosylation network starting from receptor glycotransferases, with the information of protein-protein interactions and gene expression profile of OGT, substrates and OGT-interacting proteins in LIHC. We present the clustering analysis for OGT-interacting proteins in Liver. The OGT were involved in regulation of insulin receptor signaling pathway and in response to insulin process. The biological processes investigation revealed that the second group of proteins were involved in positive regulation of transcription from RNA polymerase II promoter,which has the same function as OGT. KEGG pathways of the second group of proteins is biased toward the Insulin resistance. Insulin resistance is a condition where cells become resistant to the effects of insulin. It is often found in people with health disorders, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular diseases. High glucose and insulin levels may promote liver tumor growth. A case study has demonstrated that the proposed method could be a feasible means of conducting preliminary analyses of protein O-GlcNAcylation based on clustering analysis for OGT-interacting proteins in liver hepatocellular carcinoma (LIHC) . |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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