Structure and function of complement activating enzyme complexes:: C1 and MBL-MASPs

The complement system is a major effector arm of the immune defense contributing to the destruction of invading pathogens. There are three possible routes of complement cascade activation: the classical, the alternative and the lectin pathways. The activation of the classical and lectin pathways is initiated by supramolecular complexes, which resemble each other. Each complex has a recognition subunit (Clq in the classical and mannose-binding lectin (NBL) in the lectin pathway), which associates with serine protease zymogens (Clq with Clr and Cls, and MBL with MBL-associated serine proteases: MASP-1, MASP-2) to form the Cl and MBL-MASPs complexes, respectively. As the recognition subunits bind to activator structures, subsequent activation of the serine protease zymogens occurs. The precise structure of the complexes and the exact mechanism of their activation have not been solved, yet. In this review we summarize the recent advances about the structure arid function of the individual subcomponents of both complexes achieved by genetic engineering, molecular modeling, physico-chemical and functional studies. Special emphasis will be laid on the serine proteases: the role of the individual domains in the assembly of the Cls-Clr-Clr Cls tetramer and in the control of the protease activity will be discussed. We will then focus on recent functional models of the supramolecular complexes. The question of how a non-enzymatic signal (the binding of Clq or MBL to activators) can be converted into enzymatic events (activation of serine protease zymogens) will be addressed. The similarities and differences between Cl and MBL-MASPs will also be discussed.