The impaired FI degradation of mutant C3 molecules identified in aHUS patients can be rationalized by crystal structures of C3b-FH complexes. (A) The structure of C3b in complex with FH CCP domains 1 to 4⁶  combined with that of C3d in complex with FH CCP19-20 and a model GAG.⁷  C3d is a final degradation product of C3b, comprising basically only the thioester-containing domain (TED). Notice that the 2 extremes of FH may bind to the same C3b molecule with the intervening CCP domains looping out,⁸  but simultaneous interaction of FH with 2 activator-bound C3b molecules cannot be excluded either. FH CCP1-4 is recognized by 4 MG domains, the CUB domain, and the TED in C3b, whereas FH CCP19-20 is only contacting the C3b TED. An additional complication is that FH CCP19 interacts with the C3b TED, whereas FH CCP20 can interact with host cell membrane-linked GAG as indicated here or a nearby molecule of C3d.⁹  (B) A large number of mutant C3 residues identified in aHUS patients by Schramm et al give rise to lower cofactor activity of FH and MCP (colored circles). They are all located directly in or near to the binding interface for FH on C3b (blue residues). The figure was prepared with PyMOL¹⁰  by the combination of Protein Data Bank ID codes 4ONT⁷  and 2WII.⁶