Glycosaminoglycans (GAGs) are complex polysaccharides found in abundance at the cell-extracellular matrix (ECM) interface of eukaryotic cells. There has been a paradigm shift in understanding the importance of the dynamic nature of the cell-ECM interactions (historically the ECM was considered an inert material that hydrated the cells) in influencing phenotype at cellular and higher order tissue and organ levels. At the heart of this paradigm are the specific interactions between the chemically heterogeneous GAGs and numerous proteins in the extracellular environment. Thus, understanding the structure-function relationship of GAGs has gained importance both as a fundamental field and for its potential in identification of novel therapeutic targets. However, progress towards this goal has been limited in the past due to the polydispersity and chemical heterogeneity of GAGs that posed numerous challenges for their isolation and characterization. For several years, we have focused our efforts in addressing these challenges to develop enzymatic tools for predictable depolymerization of GAGs to decode their sequence information as well as sensitive analytical techniques to accurately detect and characterize extremely small amounts of GAGs available from cells or tissues. Focusing on the 2 important classes of GAGs viz. HSGAGs and CSGAGs we have successfully demonstrated the utility of our tools to develop rapid and robust technologies for sequencing GAGs. In this study we seek to expand on the development of our tools to focus on biochemical and biological aspects of HSGAG and CSGAG structure-function relationships. Finally, we seek to develop a database platform to capture and disseminate information and data pertaining to GAG structure function relationships which is a novel approach in the context of the GAG research area. We believe that our study would truly accelerate the progress of understanding GAG-structure-function relationships in fundamental biological processes-a research area that is gaining increasing importance.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG1-CB-G (04))
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Marino, Pamela
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Massachusetts Institute of Technology
Engineering (All Types)
Schools of Engineering
United States
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Tharakaraman, Kannan; Watanabe, Satoru; Chan, Kuan Rong et al. (2018) Rational Engineering and Characterization of an mAb that Neutralizes Zika Virus by Targeting a Mutationally Constrained Quaternary Epitope. Cell Host Microbe 23:618-627.e6
Raguram, Aditya; Sasisekharan, V; Sasisekharan, Ram (2017) AChiralPentagonalPolyhedralFramework forCharacterizingVirusCapsidStructures. Trends Microbiol 25:438-446
Ramakrishnan, Boopathy; Viswanathan, Karthik; Tharakaraman, Kannan et al. (2016) A Structural and Mathematical Modeling Analysis of the Likelihood of Antibody-Dependent Enhancement in Influenza. Trends Microbiol 24:933-943
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Shriver, Zachary; Sasisekharan, Ram (2015) Capillary electrophoretic analysis of isolated sulfated polysaccharides to characterize pharmaceutical products. Methods Mol Biol 1229:161-71
Zhu, Xueyong; Viswanathan, Karthik; Raman, Rahul et al. (2015) Structural Basis for a Switch in Receptor Binding Specificity of Two H5N1 Hemagglutinin Mutants. Cell Rep 13:1683-91
Robinson, Luke N; Tharakaraman, Kannan; Rowley, Kirk J et al. (2015) Structure-Guided Design of an Anti-dengue Antibody Directed to a Non-immunodominant Epitope. Cell 162:493-504
Lakdawala, Seema S; Jayaraman, Akila; Halpin, Rebecca A et al. (2015) The soft palate is an important site of adaptation for transmissible influenza viruses. Nature 526:122-5
Raman, Rahul; Tharakaraman, Kannan; Shriver, Zachary et al. (2014) Glycan receptor specificity as a useful tool for characterization and surveillance of influenza A virus. Trends Microbiol 22:632-41
Shriver, Zachary; Sasisekharan, Ram (2013) Heparin sensing: blue-chip binding. Nat Chem 5:644-6

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