Structure and flexibility of the multiple domain proteins that regulate complement activation

• Published in: Immunological reviews 2001-04, Vol.180 (1), p.146-161
• Main Authors: Kirkitadze, Marina D., Barlow, Paul N.
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Antigens, CD - chemistry; Antigens, CD - physiology; CD55 Antigens - chemistry; CD55 Antigens - physiology; Complement Activation; complement control protein; Complement Factor B - chemistry; Complement Factor B - physiology; Complement Factor H - chemistry; Complement Factor H - physiology; Consensus Sequence; Humans; Integrin alphaXbeta2 - chemistry; Integrin alphaXbeta2 - physiology; Magnetic Resonance Spectroscopy; Membrane Cofactor Protein; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - physiology; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Receptors, Complement 3b - chemistry; Receptors, Complement 3b - physiology; Receptors, Complement 3d - chemistry; Receptors, Complement 3d - physiology; Sequence Alignment; Sequence Homology, Amino Acid; Structure-Activity Relationship; Viral Proteins - chemistry; Viral Proteins - physiology
• ISSN: 0105-2896; 1600-065X
• DOI: 10.1034/j.1600-065X.2001.1800113.x

In this review we summarise more than 10 years of biophysical exploration into the structural biology of the regulators of complement activation (RCA). The five human proteins responsible for regulation of the early events of complement are homologous and are composed largely from building blocks called “complement control protein (CCP) modules”. Unlike most multiple domain proteins they do not contain any of the other widely occurring module types. This apparent simplicity of RCA structure, however, is belied by their sophistication of function. In fact, the structures of the individual CCP modules exhibit wide variations on a common theme while the extent and nature of intermodular connections is diverse. Some neighbouring modules within a protein stabilise each other and some co‐operate to form specific binding surfaces. The degree of true “modularity” of CCPs is open to debate. The study of RCA proteins clearly illustrates the value of combining complementary structural biology techniques. The results could have implications for folding, evolution, flexibility and structure–function relationships of other molecules in the large, diverse and little understood category of multiple domain proteins. Work in the Barlow laboratory was supported by the Medical Research Council and the Biotechnology and Biological Sciences Research Council of the UK and by the Wellcome Trust. MDK was supported by the Human Frontiers Science Program.