Khan, S.U. (2011) Solution structures of gycosaminoglycans and their interactions with complement factor H. Doctoral thesis, UCL (University College London).
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Factor H (FH), a complement regulatory protein comprised of 20 SCR domains, is able to discriminate host from pathogen cell surfaces by recognising glycosaminoglycans such as heparan sulphate on host cells to protect these from complement attack. Heparin is an analogue of HS. FH has heparin and HS binding sites located at SCR-6/8 and SCR-19/20. While the structure of FH is known from Xray solution scattering and analytical ultracentrifugation (AUC), the effects of heparin and HS on intact FH are not yet known. To evaluate the interactions with FH, solution structures of heparin fragments were determined by a combination of Xray solution scattering, AUC and constrained scattering modelling. These results revealed that heparin fragments starting from dp18 progressively show higher degrees of bending up to dp36, and resemble known crystal structures of heparinprotein complexes. Similar structural studies on similar-sized HS fragments showed that HS fragments exhibit more bent structures than heparin. This greater bending in HS fragments might be due to the reduced degree of sulphation in HS molecules. To assess the effect of heparin and HS fragments on intact FH, FH was studied in the presence of a range of purified heparin and HS fragments by scattering and AUC. The smallest heparin fragments showed little effect on the radius of gyration RG values of FH. Dramatic increases in the RG values were seen with the larger heparin sizes, and both AUC and scattering showed that a series of large but compact complexes were formed. In the presence of HS, smaller increases in oligomer formation were observed. The heparin- and HS-induced formation of oligomers in FH provide a first molecular picture of how FH may interact with host cell surfaces, and may facilitate an improved understanding of how extracellular deposits form on Bruch’s membrane during the development of age-related macular degeneration.
|Title:||Solution structures of gycosaminoglycans and their interactions with complement factor H|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Structural and Molecular Biology|
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