Proposed structure of the F' allotype of human CR1. Loss of a C3b binding site may be associated with altered function.

Human CR1 is composed of tandem long homologous repeating (LHR) segments that encode separate binding sites for C3b or C4b. Homologous recombination with unequal crossover has been proposed as the genetic mechanism that gave rise to the CR1 alleles that differed in their total numbers of LHR. The F allotype has four LHR, named LHR-A, -B, -C, -D, 5' to 3'. The site in LHR-A preferentially binds C4b and those in LHR-B and -C prefer C3b. A previous study revealed the presence of a fifth LHR with sequences similar to LHR-B and a third C3b binding site in the S allotype of higher m.w. In the present study, an 18-kb EcoRV fragment that was associated with the expression of the lower m.w. F' allotype hybridized with a unique pattern of cDNA and intron probes specific for LHR-C. Deletion of LHR-B and one C3b binding site was proposed as the mechanism for the appearance of this F'-specific fragment. Functional differences among the CR1 variants were sought by comparative analyses of soluble rCR1 having one, two or three C3b binding sites. Although these three variants did not exhibit any significant differences in their capacities to act as cofactors for the cleavage of monomeric C3b, their relative affinities for dimeric ligand varied more than 100-fold. Furthermore, the variant with only one C3b binding site was at least 10-fold less effective in the inhibition of the alternative pathway C3 and C5 convertases. These observations suggested that the F' allotype may be impaired in its capacity to bind opsonized immune complexes, to inhibit the formation of the alternative pathway C3 and C5 convertases, and perhaps to mediate other CR1-dependent cellular responses.