Structural basis for engagement by complement factor H of C3b on a self surface

Abstract

Complement factor H (FH) binds complement 3b and promotes the stepwise degradation of C3b to C3d, protecting self cells from being mistakenly recognized as foreign. A previous structure showed how CCP modules 1–4 of FH bind C3b; this study now shows the interaction of CCP modules 19–20 with C3d and builds a model for the interaction of the complete FH molecule with C3b. Complement factor H (FH) attenuates C3b molecules tethered by their thioester domains to self surfaces and thereby protects host tissues. Factor H is a cofactor for initial C3b proteolysis that ultimately yields a surface-attached fragment (C3d) corresponding to the thioester domain. We used NMR and X-ray crystallography to study the C3d–FH19–20 complex in atomic detail and identify glycosaminoglycan-binding residues in factor H module 20 of the C3d–FH19–20 complex. Mutagenesis justified the merging of the C3d–FH19–20 structure with an existing C3b–FH1–4 crystal structure. We concatenated the merged structure with the available FH6–8 crystal structure and new SAXS-derived FH1–4, FH8–15 and FH15–19 envelopes. The combined data are consistent with a bent-back factor H molecule that binds through its termini to two sites on one C3b molecule and simultaneously to adjacent polyanionic host-surface markers.