Molecular mechanisms of complement activation, regulation and evasion

Abstract

The complement system of our immune defense can rapidly recognize and eliminate pathogens in blood. Activation of complement depends on enzymatic complexes, known as C3 convertases, which are short lived and dissociate irreversibly. Staphylococcus aureus secretes a small protein (named SCIN) that suppresses the complement amplification by directly binding to C3 convertases and freezing these protease complexes in an inactive state. We reconstituted, crystallized and determined the structure of the stable C3 convertase-SCIN complex. The resulting structure shows an arrangement of dimeric convertases bridged by two SCIN molecules. The data give unprecedented insights into the activation and substrate specificity of this protease complex. Moreover, it shows highly specific host-pathogen interactions that explain a sophisticated evasion mechanism applied by S.aureus. Over-activation of complement can also be deleterious as it may cause serious damage to host cells and tissues. Thus, the efficacy of the complement-mediated immune response relies on a delicate balance between activation and regulation. Mutants and polymorphisms in the genes of complement regulators are prone to develop renal diseases and age-related macular degeneration. Complement factor H is the major soluble host regulator. The N-terminal four domains (FH1-4) possess the regulatory activity. We co-crystallized this fragment with its ligand C3b. The structure shows an extensive and discontinuous interface, which is in agreement with the functional data. We extended our structural studies to host complement regulators other than factor H and to viral homologues to address the generality of the observations and interpretations derived from C3b-FH(1-4) structure. Our results together with mutagenesis and functional data, which provide a fascinating insight into complement regulation and a comprehensive view of the molecular mechanisms underlying the regulatory activities.