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Comparable stabilisation, structural changes and activities can be induced in FGF by a variety of HS and non-GAG analogues: Implications for sequence-activity relationships

DOI: 10.1039/C0OB00246A DOI Help

Authors: Timothy Rudd (University of Liverpool) , Katarzyna Uniewicz (University of Liverpool) , Alessandro Ori (University of Liverpool) , Scott Guimond (University of Liverpool) , Mark Skidmore (University of Liverpool) , Davide Gaudesi (Istituto di Ricerche Chimiche e Biochimiche “G. Ronzoni”) , Rouyan Xu (University of Liverpool) , Jerry E. Turnbull (University of Liverpool) , Marco Guerrini (Istituto di Ricerche Chimiche e Biochimiche “G. Ronzoni”) , Giangiacomo Torri (Istituto di Ricerche Chimiche e Biochimiche “G. Ronzoni”) , Guiliano Siligardi (Diamond Light Source) , Mark C. Wilkinson (University of Liverpool) , David Fernig (University of Liverpool) , Edwin Yates (University of Liverpool)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Organic & Biomolecular Chemistry

State: Published (Approved)
Published: September 2010

Abstract: The activities of heparan sulfate (HS) and heparin do not correlate simply with sulfation levels or sequence. The alternative hypothesis, that appropriate charge and conformational characteristics for protein binding and activity can be provided by other sequences in heparan sulfate and, possibly, also in unrelated sulfated polysaccharides, is explored. Differential scanning fluorimetry was used to measure the thermo-stabilisation bestowed by modified heparin polysaccharides (proxies for heparan sulfate) on fibroblast growth factor-1 (FGF-1) and fibroblast growth factor -2 (FGF-2), prototypical heparan sulfate -binding proteins, revealing varied abilities and primary sequence-activity redundancy. The effect of substitution pattern on the heparin/heparan sulfate backbone was explored using principal component analysis of 13C NMR chemical shift data for homogeneously modified heparin polysaccharides revealing complex conformational effects. No simple relationship emerged between these polysaccharides, with their distinct charge distributions and geometries, and their ability to signal. Other, structurally unrelated sulfated polysaccharides were also able to support signalling. These influenced FGF stabilisation in a similar manner to the HS analogues and provided analogous cell signaling activity. For FGF-1, but not FGF-2, signaling correlated strongly with protein stabilisation and circular dichroism spectroscopy demonstrated that some non-HS polysaccharides invoked comparable secondary structural changes to those induced by heparin. Active conformations can readily be found in several heparin derivatives, as well as among non-HS polysaccharides, which comprise unrelated primary sequences, confirming the hypothesis and implying that the level of unique information contained in HS sequences may be much lower than previously thought.

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: B23-Circular Dichroism

Added On: 22/09/2010 13:51

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