Structure–function relationships of complement receptor type 1

Abstract

Human complement receptor type 1 (CR1) is a large, multifunctional glycoprotein which is a member of the regulators of complement activation family. Like other members of this family, it is composed mainly of tandemly arranged modules, each about 60-70 amino acids long, known as complement control protein repeats (CCPs). Each domain folds independently and contains a hydrophobic core wrapped in beta sheets. These domains mediate interactions with C3/C4-derived fragments. CR1 is the most versatile inhibitor of both classical and alternative pathway C3 and C5 convertases due to its decay-accelerating activity and co-factor activity for C3b/C4b cleavage. Moreover, CR1 plays a major role in immune complex clearance due to its high affinity for C3b and C4b. CR1 is an excellent model to study structure-function relationships because its functions are mediated by two distinct but highly homologous sites, each composed of three CCPs. CR1 derivatives carrying just one active site were used to define critical sequences/amino acids. This was achieved by testing functional profiles of the proteins carrying a mutated active site produced by substituting peptides/amino acids with their counterparts from the other site. These mutated proteins, of which we analyzed over 100, permitted the fine mapping of the functional sites. CR1 on primate erythrocytes varies in size. In most cases it is smaller and has fewer active sites than does human CR1. This variation was used to determine that increased copy number (3,000 to 20,000 versus 300 for human CR1) compensates for a smaller size. Moreover, studies of primate CR1 led to the finding that subtle differences in the critical areas, as compared to human sites, produce active sites with a broader functional repertoire. These alterations ensure that short CR1 forms possess similar biologic activities to the large CR1 forms. There is much interest in producing therapeutic agents to inhibit unwanted complement activation. Based on these structure-function analyses, smaller and more potent complement inhibitors derived from CR1 can be produced.

The Virulence Function of Streptococcus pneumoniae Surface Protein A Involves Inhibition of Complement Activation and Impairment of Complement Receptor-Mediated Protection

“…Anti-phosphocholine Abs are known to be protective against pneumococcal infection (29, 30); thus, CR1/2 Ϫ/Ϫ mice are probably highly susceptible to the normally avirulent PspA Ϫ pneumococci, because, on the one hand, they lack CR1/2 and, on the other, they have reduced titers of this (and perhaps other) protective Abs. CR1 probably also interacts with C1q and MBL (12)(13)(14), and CR1 and Fc receptors exert synergetic effects to enhance phagocytosis (31), so the host defense role of CR1/2 in mice infected with JY1119 probably has additional complexity and importance. The relative importance of factor H-mediated clearance of opsonized bacteria by platelets, which presumably direct uptake of the organism by the liver and spleen (32), also remains to be determined.…”

“…CR1 reportedly has high affinity for C3b and lower affinity for iC3b, and also binds C4b, C1q, and MBL (12)(13)(14). Likewise, murine CR1 has binding sites for both C3b and C4b (15,16).…”

Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand

“…CR1 also mediates rosetting through its interaction with PfEMP-1, a parasite-derived variant erythrocyte membrane protein (10). On the erythrocyte surface, CR1 is present as a ∼190-to 280-kDa single-chain transmembrane glycoprotein bearing the Knops blood group (11).…”

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

“…CR1 on erythrocytes has a major role in the clearance of C3b/C4b-opsonized immune complexes from the circulation. It also acts as a regulator of complement by accelerating the decay of C3 and C5 convertases and by serving as a cofactor in factor I-mediated cleavage of C3b/C4b to iC3b/iC4b and subsequently to C3d/C4d, which are ligands for other complement receptors types of the Ig superfamily, CR2, CR3, and CR4 (11). Additional CR1 ligands include C1q (12), MBL (13), and two Plasmodium falciparum proteins, the erythrocyte membrane protein 1 (PfEMP1) and the reticulocyte-binding protein homolog 4 (PfRh4) involved in rosette formation between infected and noninfected erythrocytes and sialic acid-independent cell invasion, respectively (14,15).…”