Heparan sulfate-protein interactions: therapeutic potential through structure-function insights.
Heparin and the related glycosaminoglycan, heparan sulfate, bind a myriad of proteins. The structural diversity of heparin and heparan sulfates is enormous, but differences in the conformational flexibility of the monosaccharide constituents add extra complexity and may influence protein binding. Silencing genes for heparin/ heparan sulfate biosynthetic enzymes profoundly affects mammalian development. Thus, altering the structure of heparan sulfate chains can alter protein binding and embryo development. Different heparan sulfate structures are located in particular tissue sites, and these structures are recognised by different sets of proteins. Regulation of certain heparan sulfate-protein interactions by pH or cations is described. Heparin/heparan sulfate structures are viewed as potential therapeutics for a variety of diseases. An understanding at the molecular and functional levels of the specificity and affinity of heparan sulfate-protein interactions is crucial for designing heparin-inspired drugs. How the development of synthesis techniques is facilitating structure-function analyses and drug development is discussed.
Coombe
D R
DR
Molecular Immunology, School of Biomedical Sciences, Curtin University of Technology, Level 5 MRF Building, Rear 50 Murray Street, Perth 6000, Western Australia, Australia. d.coombe@curtin.edu.au
Kett
W C
WC
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006493:Heparin / Q000737:chemistry / Q000627:therapeutic use; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D006497:Heparan Sulfate