The Department of Biomedicine

BBB seminar: Marion Kusche-Gullberg

Heparan sulfate, a coordinator of signaling pathways: assembly of ligand binding sites

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Marion Kusche-Gullberg
Section of Physiology, Department of Biomedicine, University of Bergen

Heparan sulfate, a sulfated polysaccharide with a highly varied structure, plays an important role in several cellular processes, including normal embryonic development, wound healing and inflammation. The biological activities depend on the ability of heparan sulfate to bind proteins in a selective fashion. The emerging view is that a cell can respond to its microenvironment by dynamically regulating heparan sulfate fine structure at the cell surface and in the extracellular matrix. However, the mechanism by which specific protein-binding sequences are generated within the heparan sulfate chains and the role these sequences play in protein signaling in normal and diseased conditions is not well understood. Defects in enzymes involved in heparan sulfate biosynthesis result in different abnormalities including formation of bone tumors, abnormal skeletal and kidney development and eye defects. To understand the mechanisms generating specific protein-binding structures, it is essential that we expand our understanding of the regulation of the heparan sulfate biosynthetic machinery.

Over the past few years we have been characterizing key-enzymes involved in heparan sulfate biosynthesis with respect to their catalytic properties and substrate specificities, their mode of cooperation and interaction with other enzymes in the biosynthetic machinery and their gene structure and expression. In the seminar some of our ongoing projects will be presented.

Selected references:

Smeds, E., Habuchi, H., Do, A.-T, Hjertson, E., Grundberg, H, Kimata, K., Lindahl, U. and Kusche-Gullberg, M. Substrate specificities of mouse heparan sulfate glucosaminyl 6-O-sulfotransferases. (2003) Biochem. J. 372, 371-380
Kusche-Gullberg, M and Kjellén L. Sulfotransferases in glycosaminoglycan biosynthesis. (2003) Curr. Opin. Struct. Biol. 13, 1-7
Busse, M. and Kusche-Gullberg, M. In vitro polymerization of heparan sulfate backbone structure by the EXT Proteins. (2003) J. Biol. Chem. 278, 41333-41337
Yamada, S., Busse, M., Ueno, M., Kelly, O.G., Skarnes, W.C., Sugahara, K., and Kusche-Gullberg, M. Embryonic fibroblasts with a gene trap mutation in Ext1 produce short heparan sulfate chains. (2004) J. Biol. Chem. 279, 32134-32141