Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces

To discriminate between self and non-self surfaces facilitate immune surveillance, the complement system relies on interplay surface-directed activators regulators. The dimeric modulator FHR-1 is hypothesized to competitively remove regulator FH from that strongly fix opsonic C3b molecules—a process known as “deregulation.” C-terminal regions of provide basis this competition. They contain binding sites for host surface markers are identical except two substitutions: S1191L V1197A (i.e., “SV”; “LA”). Intriguingly, an variant featuring “SV” combination predisposes atypical hemolytic uremic syndrome (aHUS). functional impact these mutations (de)regulation, their pathophysiological consequences, have largely remained elusive. We addressed questions using recombinantly expressed wildtype, mutated, truncated versions FH. “LA” substitutions did not affect glycosaminoglycan recognition had only a small effect binding. In contrast, amino acids substantially affected ?2,3-linked sialic markers, with S-to-L substitution causing almost complete loss recognition. Even acid-binding constructs, notable deregulation was detected foreign cells. aHUS-associated mutation converts into acid binder which, supported by its nature, enables excessive and, thus, activation surfaces. While we also observed inhibitory activities C3 C5 convertases, high concentrations required render physiological uncertain. conclusion, SV-to-LA in diminishes ability results molecule moderately deregulates Such occurs host/host-like recruit Conversion potentiates deregulatory capacity thus explains pathophysiology variant.