The Molecular Mechanisms of Complement Receptor 1—It Is Complicated

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.

Mechanistic insights into complement pathway inhibition by CR1 domain duplication

“…Understanding the interaction between receptor and ligand in the case of CR1 is important from both a biological and a drug development perspective, but is complicated by the presence of multiple ligands as well as multiple binding sites delineated by the LHR domains, and the SCR domains contained within them ( 1 ). We set out to analyze the in vitro inhibitory activity of domain variants of soluble CR1 based on CSL040 (LHR-ABC), since this protein lacks the LHR-D domain responsible for C1q, mannose binding lectin, and ficolin binding ( 6 , 7 , 8 ) and confined this work to understanding ligand binding domain utilisation in the context of the main CR1 ligands, C3b, and C4b.…”

“…Complement receptor 1 (CR1) is a type I membrane protein that acts as a central regulator of complement. Its extracellular domain is comprised of 30 short consensus repeat (SCR) domains that are grouped into four long homologous repeat (LHR) domains responsible for ligand binding and biological activity ( 1 , 2 , 3 ). These ligands have been identified as the activated complement fragments and opsonins C3b and C4b ( 4 , 5 ), which bind to LHR-A, LHR-B, and LHR-C; and C1q, mannose-binding lectin, and L-ficolin which bind to LHR-D ( 6 , 7 , 8 ).…”

“…LHR-B and LHR-C are functionally identical and are the main binding domains for C3b ( 2 , 9 ), but they also bind C4b weakly in experiments where C3b is absent ( 12 , 13 ), raising the question of whether C4b binds these domains when both ligands are present. The receptor–ligand interactions between CR1 and C3b, as well as C4b, are further complicated in that both molecules are present in plasma as monomers, dimers, and even heterodimers to mediate decay acceleration activity of C3 and C5 convertases and cofactor activity (CFA) mediated by factor I for the classical, lectin, and alternative complement pathways ( 1 ). The significantly stronger affinity of CR1 for dimeric C3b and C4b than monomeric ligands suggests a bivalent interaction between multiple LHR domains of a single CR1 molecule and each dimeric ligand ( 12 , 14 , 15 ).…”

“…Although there is some understanding of CR1 LHR domain contribution to ligand binding, CFA, and decay acceleration activity (reviewed by Hardy et al. 2023) ( 1 ), relatively few studies have been performed to understand their contribution to overall potency for the classical, lectin, and alternative pathways, as measured by either red blood cell hemolytic assays or soluble membrane attack complex formation (sC5b-9; containing the terminal complement components C5b, C6, C7, C8, and C9) using the Wieslab and similar assays. One of the earliest studies ( 14 ) demonstrated that LHR-A to LHR-C were necessary for inhibition of CHO cell lysis, with a subsequent study showing that removing the LHR-A domain from the soluble CR1 extracellular domain (desLHR-A) resulted in no difference in alternative pathway mediated erythrocyte lysis but did show a significant reduction in classical pathway lytic activity ( 16 ).…”

Alzheimer's Disease Investigated via Gene-Environment Interactions, Biochemical Pathways, Cellular Processes, and Disease Phenotype Variability

“…Variability in the age of onset, symptom severity, and disease progression among individuals carrying similar mutations in the CR1 gene can be attributed to a complicated interaction of genetic, environmental, neurobiological, cognitive, and other factors [116,130].…”