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 modeling not only allows to predict the three-dimensional structure of a protein but also helps to define its function. Careful incorporation of the experimental findings in the structural/theoretical data provides means to understand molecular mechanisms for highly complex biological systems. C4b-binding protein (C4BP) is composed of one beta-chain and seven alpha-chains essentially built from three- and eight-complement control protein (CCP) modules, respectively, followed by a non-repeat carboxy-terminal region involved in polymerization of the chains. C4BP is involved in the regulation of the complement system and interacts with many molecules such as C4b, Arp, protein S and heparin. Here, we report experimental and computer data obtained for C4BP. Protein modeling together with site directed mutagenesis indicate that R39, R64 and R66 from the C4BP alpha-chain form a key binding site for heparin, suggesting that this region could be of major importance for interaction with C4b. We also propose that the first CCP of the C4BP beta-chain displays a key hydrophobic surface of major importance for the interaction with the coagulation cofactor protein S.
Lund University, The Wallenberg Laboratory, Department of Clinical Chemistry, University Hospital, Malmö, Sweden. bruno.villoutreix@klkemi.mas.lu.se
B O
BO
Villoutreix
A M
AM
Blom
J
J
Webb
B
B
Dahlbäck
D015935:Complement C4b / Q000737:chemistry*; D003169:Complement Inactivator Proteins; D019295:Computational Biology; D003198:Computer Simulation; D006023:Glycoproteins; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011951:Receptors, Complement / Q000737:chemistry*; D013329:Structure-Activity Relationship
D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D011951:Receptors, Complement; D015935:Complement C4b