Proteoglycans ar negatively-charged glycosominoglycans covalently bound to a core protein. In hyaline cartilage, proteoglycans occur as large aggregates formed when 50-100 proteoglycan monomers bind to a single molecule of hyaluronic acid. Aggregation is necessary for maintaining healthy, functional cartilage, yet little is known about the nature of the interactions among aggregate components.
The aim of this research is to determine the solution conformation of hyaluronic acid, and to identify the features necessary for its specific interaction with core protein and link protein in the proteoglycan aggregate. The experimental approach will be high resolution, two-dimensional nuclear magnetic resonance spectroscopy (NMR), in conjunction with molecular modelling. Recent developments in NMR make it possible to determine solution conformations of molecules (molecular weight <20,000) of increasing complexity. Conformations will be based on two independent NMR parameters, scalar coupling constants and NOE intensities. The long-term objective of this research is to determine the conformations and interactions of all the components of the proteoglycan aggregate, including core and link proteins, to provide a basis for understanding why aggregation fails to osteoarthritis. Besides the immediate relevance to a serious and prevalent disease, the results of this research will contribute to our understanding of protein-carbohydrate interactions and structure-function relations in biomolecules. This project will focus on proteoglycan aggregate from rat chondrosarcoma, which provide a starting point for further studies on proteoglycans from other tissues and species.
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