Crystal structure of the catalytic domain of human complement C1s: a serine protease with a handle

C1s is the highly specific modular serine protease that mediates the proteo lytic activity of the C1 complex and thereby triggers activation of the com plement cascade. The crystal structure of a catalytic fragment from human C 1s comprising the second complement control protein (CCP2) module and the c hymotrypsinlike serine protease (SP) domain has been determined and refined to 1.7 Angstrom resolution. In the areas surrounding the active site, the SP structure reveals a restricted access to subsidiary substrate binding si tes that could be responsible for the narrow specificity of C1s. The ellips oidal CCP2 module is oriented perpendicularly to the surface of the SP doma in. This arrangement is maintained through a rigid module-domain interface involving intertwined proline- and tyrosine-rich polypeptide segments. The relative orientation of SP and CCP2 is consistent with the fact that the la tter provides additional substrate recognition sites for the C4 substrate. This structure provides a first example of a CCP-SP assembly that is conser ved in diverse extracellular proteins. Its implications in the activation m echanism of C1 are discussed.