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• W1534218212 abstract "Introduction  Fibroblast growth factors (FGFs) are a multipotent family of growth factors that are important for many biological processes, including development and wound healing. Normal, protease sensitive, prion protein (PrPC) can be converted to the protease resistant, infectious, form (PrPSc) believed to be associated with the pathogenesis of transmissible spongiform encephalopathies. FGFs signal through a family of tyrosine kinase receptors, the FGF receptors (FGFR) with the aid of heparan sulfate (HS), while the role of HS in the biology of PrPC is currently unknown, although depleting cells of HS can prevent production of PrPSc. HS, or its more highly sulfated relation heparin, can exert both positive and negative regulatory activities on a particular FGF-FGFR combination. The nature of this regulation is determined by the structure of the HS that binds to the proteins. This structure is at least partially determined by the presence of particular sulfate groups along the sugar backbone. Identification of specific sulfate groups that can regulate the activity of proteins has been a long-term goal in the field. Previously, heparins that had been completely lacking sulfates at specific positions were used to determine the binding and activity requirements for a particular protein. However, this may not necessarily allow for a full examination of the regulatory properties of HS. Here, we present a heparan sulfate analogue library produced by the partial, combinatorial desulfation of heparin. This library was the used to examine the structural properties of heparin required for FGF-1 signalling through FGFR2c as well as the interactions of HS with PrPC.Materials and methods  Porcine intestinal mucosal heparin was subjected to chemical desulfation and enzymatic cleavage. Polysaccharides and oligosaccharides derived from gel filtration chromatography and ion exchange chromatography were tested for their ability to activate FGF signalling through FGF receptors using a BaF3 assay system. Optical biosensors and cell assays were used to study the interaction of PrPC with chemically modified heparin.Results  This library possessed vastly more heterogeneity than tissue heparan sulfates, allowing for more systematic screening to help identify those minimal structural features associated with activity. This library was used to examine the different structural features in heparin that support FGF-1 signalling through FGFR2, showing that HS activity was not strictly dependant on size or charge. In addition, small, low-sulfated heparins were found to interfere with the PrPC–heparin interaction.Discussion  This supports the idea that overall structural features of the HS, rather than just the presence or absence of specific sulfate groups is important for the regulation of protein activity. Future efforts will be focused on further subfractionating the library and identifying specific structural features in HS that support FGF-1 activity through FGFR2 and other FGFRs as well as the role of HS in the normal function of prion diseases, which may allow for the generation of novel, heparin-based, therapeutics." @default.
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• W1534218212 date "2004-08-12" @default.
• W1534218212 modified "2023-10-18" @default.
• W1534218212 title "Highly diverse heparan sulfate analogue libraries: a novel resource for bioactivity screening of proteins" @default.
• W1534218212 doi "https://doi.org/10.1111/j.0959-9673.2004.0390w.x" @default.
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