New Insights into the Regulation of Complement Activation by Decay Accelerating Factor

Abstract

Decay-accelerating factor (DAF), a ubiquitously expressed GPI-anchored protein, is an intrinsic regulator of complement activation that acts to dissociate autologous C3 and C5 convertases that assemble on self cells. DAF contains four ~60 amino acid long repeats termed short consensus repeats (SCRs) or complement control protein repeats (CCPs), followed by a serine/threonine (S/T)-rich region which in turn is attached to a posttranslationally-added glycosylphosphatidylinositol (GPI)-anchor. Studies with CCP deletion mutants showed that CCPs 2 and 3 are required for classical pathway (CP) function while CCP4 is additionally required for alternative pathway (AP) function. Mutagenesis studies based on a model built from the NMR structure of homologous CCPs indicated that positively charged amino acids (R69, R96, and R100 in CCP2, and K127 in the CCP2-CCP3 linker) and hydrophobic residues primarily in CCP3 (F148, F169, and L171) are important for DAF’s function in one or both pathways. A recent NMR solution structure of CCPs 2–3, the crystal structure of CCPs 3–4, and the crystal structure of all four CCPs have allowed mapping of the mutagenesis data on DAF’s 3D structure but have raised a controversy over the flexibility of its junctions, particularly CCPs 2–3, and the roles in function of certain amino acids, particularly the positively charged residues between CCPs 2 and 3. Work on DAF’s ligands indicates that DAF interacts with Y338A and Y327A residues in the von Willibrand factor type A (vWFA) domains of factor B and C2, respectively. Current work is proceeding toward understanding DAF’s role as a receptor for E. coli expressing AFA and Dr adhesions and certain picorna viruses. The recent availability of Daf1 knock-out mice has allowed studies of its in vivo function in diseases such as myasthenia gravis and autoimmune renal disease.Key wordsDecay-accelerating factor (DAF or CD55)short consensus repeatscomplement control protein repeatssushi (SCR/ CCP/ sushi)C3/C5 convertases