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