Trends in Immunology
Structure and activation of the C1 complex of complement: unraveling the puzzle
Section snippets
A refined, three-dimensional model of C1
In addition to mediating the recognition function of the C1 complex, C1q also provides a scaffold for proper folding of the catalytic subunit C1s–C1r–C1r–C1s. Therefore, correct modeling of this protein is a prerequisite for building a precise three-dimensional model of C1. Resolution of the X-ray structure of the C1q globular head has revealed the arrangement of the three subunits (A, B, C clockwise, when the head is viewed from the top), enabling us to derive a three-dimensional model of the
C1 activation: a random, mechanical process?
In addition to revealing the details of their structure, X-ray analysis of the C1r and C1s catalytic regions also provides precise insights into the molecular mechanisms underlying C1 activation. From a functional standpoint, the most intriguing feature of the C1r catalytic region head-to-tail structure [23] is that the catalytic site of one monomer and the activation site of the other lie at opposite ends of the dimer (Figure 1d). This configuration probably represents a resting state of the
Structural basis for the versatile recognition function of C1q
One of the most striking properties of C1q lies in its ability to recognize an amazing variety of targets, including immunoglobulins, CRP, β-amyloid fibrils, the prion protein, lipid A, DNA, various microorganisms and apoptotic cells. There is no obvious structural feature shared by these diverse ligands, however, the fact that many polyionic structures are recognized by C1q [1], suggests that it might function as a charge pattern recognition molecule. The X-ray structure of the heterotrimeric
Conclusions and perspectives
The combined use of a dissection strategy and of structural biology techniques has led to a refined, three-dimensional model of the C1 complex of complement, providing for the first time a sound structural basis for the mechanisms underlying its activation process and its recognition properties. Understanding the details of the assembly and function of C1 at the atomic level will now require resolution of the remaining unknown three-dimensional structures within C1, and the use of site-directed
Acknowledgements
We are indebted to Isabelle Bally, Beate Bersch, Monika Budayova-Spano, Claudine Darnault, Jordi Juanhuix, Monique Lacroix and David Pignol, who contributed to many of the studies reported in this review.
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