The role of properdin in the assembly of the alternative pathway C3 convertases of complement.
Complement is a powerful host defense system that contributes to both innate and acquired immunity. There are three pathways of complement activation, the classical pathway, lectin pathway, and alternative pathway. Each generates a C3 convertase, a serine protease that cleaves the central complement protein, C3. Nearly all the biological consequences of complement are dependent on the resulting cleavage products. Properdin is a positive regulator of complement activation that stabilizes the alternative pathway convertases (C3bBb). Properdin is composed of multiple identical protein subunits, with each subunit carrying a separate ligand-binding site. Previous reports suggest that properdin function depends on multiple interactions between its subunits with its ligands. In this study I used surface plasmon resonance assays to examine properdin interactions with C3b and factor B. I demonstrated that properdin promotes the association of C3b with factor B and provides a focal point for the assembly of C3bBb on a surface. I also found that properdin binds to preformed alternative pathway C3 convertases. These findings support a model in which properdin, bound to a target surface via C3b, iC3b, or other ligands, can use its unoccupied C3b-binding sites as receptors for nascent C3b, bystander C3b, or pre-formed C3bB and C3bBb complexes. New C3bP and C3bBP intermediates can lead to in situ assembly of C3bBbP. The full stabilizing effect of properdin on C3bBb would be attained as properdin binds more than one ligand at a time, forming a lattice of properdin: ligand interactions bound to a surface scaffold.
Hourcade
Dennis E
DE
Department of Medicine/Division of Rheumatology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110-1093, USA. dhourcad@im.wustl.edu
D001665:Binding Sites; D015374:Biosensing Techniques; D003167:Complement Activation; D050577:Complement C3-C5 Convertases / Q000737:chemistry*; D003165:Complement System Proteins / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D011414:Properdin / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry; D020349:Surface Plasmon Resonance; D013499:Surface Properties; D013997:Time Factors
D008024:Ligands; D011414:Properdin; D003165:Complement System Proteins; D050577:Complement C3-C5 Convertases; D012697:Serine Endopeptidases