Structure-function relationships of complement receptor type 1

Human complement receptor type 1 (CR1) is a large, multi-functional glycopr otein which is a member of the regulators of complement activation family L ike other members of this family, it is composed mainly of tandemly arrange d modules, each about 60-70 nine acids long, known as complement control pr otein repeats (CCPs). Each domain folds independently and contains a hydrop hobic core wrapped in beta sheets. These domains mediate interactions with C3/C4-derived fragments. CR1 is the most versatile inhibitor of both classi cal and alternative pathway C3 and C5 convertases due to its decay-accelera ting activity and co-factor activity for C3b/C4b cleavage. Moreover, CR1 pl ays a major role in immune complex clearance due to its high affinity for C 3b and C4b. CR1 is an excellent model to study structure-function relations hips because its functions are mediated by two distinct but highly homologo us sites, each composed of three CCPs. CR1 derivatives carrying just one ac tive site were used to define critical sequences/amino adds. This was achie ved by testing functional profiles of the proteins carrying a mutated activ e site produced by substituting peptides/amino acids with their counterpart s from the other site. These mutated proteins, of which we analyzed over 10 0, permitted the fine mapping of the functional sites. CR1 on primate eryth rocytes varies in size. In most cases it is smaller and has fewer active si tes than does human CR1. This variation was used to determine that increase d 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 subt le differences in the critical areas, as compared to human sites, produce a ctive sites with a broader functional repertoire. These alterations ensure that short CR1 forms possess similar biologic activities to the large CR1 f orms. There is much interest in producing therapeutic agents to inhibit unw anted complement activation. Based on these structure-function analyses, sm aller and more potent complement inhibitors derived from CR1 can be produce d.