John P. Atkinson

Backbone dynamics of complement control protein (CCP) modules reveals mobility in binding surfaces.

The regulators of complement activation (RCA) are critical to health and disease because their role is to ensure that a complement‐mediated immune response to infection is proportionate and targeted. Each protein contains an uninterrupted array of from four to 30 examples of the very widely occurring complement control protein (CCP, or sushi) module. The CCP modules mediate specific protein–protein and protein–carbohydrate interactions that are key to the biological function of the RCA and, paradoxically, provide binding sites for numerous pathogens. Although structural and mutagenesis studies of CCP modules have addressed some aspects of molecular recognition, there have been no studies of the role of molecular dynamics in the interaction of CCP modules with their binding partners. NMR has now been used in the first full characterization of the backbone dynamics of CCP modules. The dynamics of two individual modules—the 16th of the 30 modules of complement receptor type 1 (CD35), and the N‐terminal module of membrane cofactor protein (CD46)—as well as their solution structures, are compared. Although both examples share broadly similar three‐dimensional structures, many structurally equivalent residues exhibit different amplitudes and timescales of local backbone motion. In each case, however, regions of the module‐surface implicated by mutagenesis as sites of interactions with other proteins include several mobile residues. This observation suggests further experiments to explore binding mechanisms and identify new binding sites.

The Human Complement System: Basic Concepts and Clinical Relevance

Abstract The complement system is a key player in innate immunity and a major effector arm of humoral immunity. Its activating components are a group of plasma proteins, whose triggering consists of a series of sequential protease-based steps similar to the coagulation, fibrinolytic, and contact pathways. Complement activation is linked to cellular responses by the recognition of cleaved complement protein fragments by receptors on leukocytes and vascular cells. The three primary roles of complement in host defense against infection are to (1) activate an inflammatory response; (2) opsonize microbial pathogens for immune adherence; and (3) damage membranes, including lysis of susceptible organisms. The complement cascade is amplified at several steps so that it has the potential to induce a rapid and massive opsonic and inflammatory response. Complement activation is normally highly targeted and strictly regulated to focus this response. However, complement activation also contributes to tissue injury in infectious, autoimmune, and acute and chronic inflammatory diseases. This chapter gives an overview of the “workings” of the complement system, a brief review of complement deficiency, and discussion of the role of complement in diseases of inflammation, autoimmunity, and debris disposal.