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

In this review we summarise more than 10 years of biophysical exploration i nto the structural biology of the regulators of complement activation (RCA) . The live human proteins responsible for regulation of the early events of complement are homologous and are composed largely from building blocks ca lled "complement control protein (CCP) modules". Unlike most multiple domai n proteins they donor contain any of the other widely occurring module type s. This apparent simplicity of RCA structure, however, is belied by their s ophistication of function. In fact, the structures of the individual CCP mo dules exhibit nide 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 st udy of RCA proteins clearly illustrates the value of combining complementar y structural biology techniques. The results could have implications for fo lding, evolution, flexibility and structure-function relationships of other molecules in the large, diverse and little understood category of multiple domain proteins.