Complement Receptor 1 (CR1)

Complement Receptors of Complement System: CR1 Structure

Complement receptor type 1 (CR1, CD35) is a 210-290 kDa membrane glycoprotein with specificity for the complement products C3b, C4b and, with lower affinity, iC3b.

CR1 shares structural similarities with a group of proteins, including factor H, C4-binding protein (C4bp), decayaccelerating factor (DAF), membrane cofactor protein (MCP), CR2, C1r, IL-2 receptor, β2-glycoprotein 1, haptoglobin a chain and factor XIIIb, many of which are involved in the control of complement activity. These proteins are known as the regulators of complement activation (RCA) family.

The extracellular domain of CR1 consists of an array of 30 or more homologous units (short consensus repeats, SCRs) comprising of 60-65 amino acids, of which 10-15 are highly conserved in all members of the family; including four half-cystines linking in a first-third, second-fourth arrangement to create a triple-loop structure within each SCR. Distinctive for CR1 is the arrangement of the SCRs in three to six long homologous repeats (LHR) comprising seven SCR units and displaying 70-95% identity between each LHR. The transmembrane region of CR1 consists of 25 hydrophobic amino acids followed by four positively charged residues and the C-terminal cytoplasmic domain consists of 39 amino acids.

Complement Receptors of Complement System: CR1 Cellular Distribution

Complement receptor type 1 (CR1, CD35) is expressed on monocytes/macrophages, neutrophils, eosinophils, basophils, natural killer (NK) cells, B cells and some T cells, as well as follicular dendritic cells (FDC), glomerular podocytes, Kupffer cells and, in the case of most primates, erythrocytes.

Although the number of CR1 molecules expressed on the erythrocytes (about 250 per cell) is 25- to 50-fold lower than that on blood leucocytes, the preponderance of erythrocytes in whole blood ensures that 85-90% of the cell-bound CR1 pool resides on these cells. The surface expression of CR1 on neutrophils is highly susceptible to modulation, being rapidly upregulated 5- to 10-fold by the chemotactic peptides fMLP and C5a-desarg, by GM-CSF and even by changes in temperature, and downregulated by 60-70% by PMA. The internal pool of CR1, responsible for the rapid upregulation, is located in smooth-surfaced vesicles distinct from the granulocyte's primary and secondary granules. A soluble form of CR1(sCR1), present in low concentration in normal plasma, is thought to arise from cleavage of membrane CR1 from blood leucocytes.

Complement Receptors of Complement System: CR1 Function

Each complement receptor type 1 (CR1, CD35) contains multiple C3b-binding sites located within the first four SCRs of each LHR and a single, high-affinity C4b-binding site in the same region of the first LHR. In addition to acting as a receptor, CR1 regulates complement activation by promoting factor I-mediated degradation of C3b to iC3b and, subsequently, C3c and C3dg, and of C4b to C4c and C4d.

CR1 triggering of activities such as phagocytosis generally requires other forms of priming or enhancing stimuli (e.g. phorbol esters, fMLP, fibronectin, C1q, mannan-binding lectin or the pulmonary surfactant protein SPA). However, induction of lactoferrin release from granulocytes and IL-1 production, nuclear translocation of nuclear factor-kB (NF-kB) and prostaglandin synthesis by monocytes occurs upon stimulation via CR1 alone. Complement receptor type 1 (CR1, CD35) has been reported to promote differentiation of activated B cells to immunoglobulin-secreting cells following antigenic stimulation. However, an equally important role for CR1 on B cells may be the conversion of antigenbound C3b to C3dg, thereby facilitating attachment of the opsonized antigen to CR2.

Complement Receptors of Complement System: CR1 Signalling

There is no evidence that complement receptor type 1 (CR1, CD35) in its nonphosphorylated, resting state, is capable of inducing signal transduction. Phosphorylation of CR1 occurs in neutrophils and monocytes (but not B cells), following activation of PKC with platelet-activating factor or PMA, and converts the receptor to an activated state, in which it is capable of triggering such activities as phagocytosis. However, the signal transduction mechanisms employed by activated CR1 have not yet been characterized.

Complement Receptors of Complement System: CR1 Reference

1. Nielsen C H, et al. (1997). The roles of complement receptors type 1 (CR1, CD35) and type 3 (CR3, CD11b/CD18) in the regulation of the immune complex‐elicited respiratory burst of polymorphonuclear leukocytes in whole blood. European journal of immunology, 27(11), 2914-2919.
2. Klickstein, et al. (1997) Complement receptor type 1 (CR1, CD35) is a receptor for C1q. Immunity 7.3 : 345-355.
3. Leslie R G Q, et al. (2009). Complement receptors. eLS.