Structural biology of the C1 complex of complement unveils the mechanisms of its activation and proteolytic activity

Cl is the multimolecular protease that triggers activation of the classical pathway of complement, a major element of antimicrobial host defense also involved in immune tolerance and various pathologies. This 790 000 Da complex is formed from the association of a recognition protein, Clq, and a catalytic subunit, the Ca2+-dependent tetramer Cls-Clr-Clr-Cls comprising two copies of each of the modular proteases Clr and Cls. Early studies mainly based on biochemical analysis and electron microscopy of Cl and its isolated components have allowed for characterization of their domain structure and led to a low-resolution model of the Cl complex in which the elongated Cls-Clr-Clr-Cls tetramer folds into a more compact, "8-shaped" conformation upon interaction with Clq. A major strategy used over the past years has been to dissect the Cl proteins into modular segments to characterize their function and solve their structure by either X-ray crystallography or nuclear magnetic resonance spectroscopy (NMR). The purpose of this review is to focus on this information, with particular emphasis on the architecture of the Cl complex and the mechanisms underlying its activation and proteolytic activity. (C) 2002 Elsevier Science Ltd. All rights reserved.