Khan, S; Fung, KW; Rodriguez, E; Patel, R; Gor, J; Mulloy, B; Perkins, SJ; (2013) The solution structure of heparan sulfate differs from that of heparin: implications for function. J Biol Chem , 288 pp. 27737-27751. 10.1074/jbc.M113.492223.

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Abstract

The highly sulfated polysaccharides heparin and heparan sulfate (HS) play key roles in the regulation of physiological and pathophysiological processes. Despite its importance, no molecular structures of free HS have been reported up to now. By combining analytical ultracentrifugation, small-angle X-ray scattering and constrained scattering modelling recently used for heparin, we have analysed the solution structures for eight purified HS fragments dp6 to dp24 corresponding to the predominantly unsulfated GlcA-GlcNAc domains of heparan sulfate. Unlike heparin, the sedimentation coefficient s20,w of HS dp6-dp24 showed a small rotor speed dependence, where similar s20,w values of 0.82 to 1.26 S (absorbance optics) and 1.05 to 1.34 S (interference optics) were determined. The corresponding X-ray scattering measurements of HS dp6-dp24 gave radii of gyration RG values from 1.03 nm to 2.82 nm, cross-sectional radii of gyration RXS values from 0.31 nm to 0.65 nm, and maximum lengths L from 3.0 nm to 10.0 nm. These data showed that HS has a longer and more bent structure than heparin. Constrained scattering modelling starting from 5,000-12,000 conformationally-randomised HS structures gave best fit dp6-dp24 molecular structures that were longer and more bent than their equivalents in heparin. Alternative fits were obtained for HS dp18 and dp24, indicating their higher bending and flexibility. We conclude that HS displays bent conformations that are significantly distinct from that for heparin. The difference is attributed to the different predominant monosaccharide sequence and reduced sulphation of HS, indicating that HS may interact differently with proteins compared to heparin.

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