Abstract
Human complement receptor 1 (CR1) is a membrane-bound regulator of complement that has been the subject of recent attempts to generate soluble therapeutic compounds comprising different fragments of its extracellular domain. This review will focus on the extracellular domain of CR1 and detail how its highly duplicated domains work both separately and together to mediate binding to its main ligands C3b and C4b, and to inhibit the classical, lectin, and alternative pathways of the complement cascade via the mechanisms of decay acceleration activity (DAA) and co-factor activity (CFA). Understanding the molecular basis of CR1 activity is made more complicated by the presence not only of multiple ligand binding domains within CR1 but also the fact that C3b and C4b can interact with CR1 as both monomers, dimers, and heterodimers. Evidence for the interaction of CR1 with additional ligands such as C1q will also be reviewed. Finally, we will bring the mechanistic understanding of CR1 activity together to provide an explanation for the differential complement pathway inhibition recently observed with CSL040, a soluble CR1-based therapeutic candidate in pre-clinical development.