Glycomics : an emerging paradigm to protein-carbohydrate interactions

Glycosaminoglycans (GAGs) are a family of complex carbohydrates whose known biological roles have dramatically increased over the recent years. It is now becoming increasingly evident that sequence specific GAG-protein interactions play critical roles in cell growth, development, angiogenesis, cancer, anticoagulation and microbial pathogenesis. Therefore it is important to understand the specificity of glycan-protein interactions and how these specific interactions influence their structure-function relationships. This thesis addresses many challenges in this emerging area of glycomics, by taking an integrated approach that couples biophysical and biochemical methods with a bioinformatics framework to represent and process sequence information content in GAGs. With this motivation the thesis is divided into 4 components 1. Using heparin/heparan sulfate GAGs (HSGAGs) - fibroblast growth factor (FGF) as a model GAG-protein system, the first part focuses on determining the structural basis of FGF oligomerization, sequence specific FGF-HSGAG interactions and FGF-receptor (FGFR) interactions which collectively influence the specificity of HSGAG mediated FGF signaling. 2. The second part focuses on developing enzymatic tools for analysis of GAGs using chondroitinase B, HSGAG 2-0 sulfatase and 3-0 sulfotransferase as model enzymes. For each of these enzymes a theoretical model for the enzyme-substrate structural complex is developed and it is coupled with the site directed mutagenesis and biochemical studies to determine its catalytic mechanism and substrate specificity. 3. To deal with the heterogeneity and high information density of GAG sequences, an informatics based approach to decode GAG sequence information has been developed.

Department dc:contributor.department

Massachusetts Institute of Technology. Biological Engineering Division.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2003

Author dc:creator

• Raman, Rahul, 1977-

Advisor dc:contributor.advisor

• Ram Sasisekharan.

• Biological Engineering Division.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/29948

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/29948