The complement regulator C4b-binding protein analyzed by molecular modeling, bioinformatics and computer-aided experimental design

Molecular modeling and bioinformatics have gained recognition as scientific disciplines of importance in the field of biomedical research. Molecular m odeling not only allows to predict the three-dimensional structure of a pro tein but also helps to define its function. Careful incorporation of the ex perimental findings in the structural/theoretical data provides means to un derstand molecular mechanisms for highly complex biological systems. C4b-bi nding protein (C4BP) is composed of one beta-chain and seven alpha-chains e ssentially built from three- and eight-complement control protein (CCP) mod ules, respectively, followed by a non-repeat carboxy-terminal region involv ed in polymerization of the chains. C4BP is involved in the regulation of t he complement system and interacts with many molecules such as C4b, Arp, pr otein S and heparin. Hen, we report experimental and computer data obtained for C4BP. Protein modeling together with site directed mutagenesis indicat e that R39, R64 and R66 from the C4BP alpha-chain form a key binding site f or heparin, suggesting that this region could be of major importance for in teraction with C4b. We also propose that the first CCP of the C4BP beta-cha in displays a key hydrophobic surface of major importance for the interacti on with the coagulation cofactor protein S. (C) 1999 Elsevier Science B.V. All rights reserved.