Title : X-ray structure of the Ca2 +-binding interaction domain of C1s
Abstract :
Insights into the assembly of the C1 complex of complement
C1, the complex that triggers the classical pathway of complement, is assembled from two modular proteases C1r and C1s and a recognition protein C1q
The N-terminal CUB1- EGF segments of C1r and C1s are key elements of the C1 architecture, because they mediate both Ca2 +-dependent C1r- C1s association and interaction with C1q
The crystal structure of the interaction domain of C1s has been solved and refined to 1.5 A resolution
The structure reveals a head-to-tail homodimer involving interactions between the CUB1 module of one monomer and the epidermal growth factor ( EGF ) module of its counterpart
A Ca2 + ion is bound to each EGF module and stabilizes both the intra- and inter-monomer interfaces
Unexpectedly, a second Ca2 + ion is bound to the distal end of each CUB1 module, through six ligands contributed by Glu45, Asp53, Asp98 , and two water molecules
These acidic residues and Tyr17 are conserved in approximately two-thirds of the CUB repertoire and define a novel, Ca2 +-binding CUB module subset
The C1s structure was used to build a model of the C1r- C1s CUB1- EGF heterodimer , which in C1 connects C1r to C1s and mediates interaction with C1q
A structural model of the C1q / C1r/C1s interface is proposed, where the rod-like collagen triple helix of C1q is accommodated into a groove along the transversal axis of the C1r- C1s heterodimer