Comparative modeling of the three CP modules of the beta-chain of C4BP and evaluation of potential sites of interaction with protein S.
A computer model of the beta-chain of C4b-binding protein (C4BP) was constructed, using the backbone fold of the NMR structures of the sixteenth CP module of factor H (H16) and of a pair of modules consisting of the fifteenth and sixteenth CPs of factor H (H15-16). The characteristic hydrophobic core responsible for dictating the three-dimensional structure of the CP family is conserved in the amino acid sequence of C4BP beta 1, beta 2 and beta 3. The distribution of the electrostatic potential shows that the model is mainly covered by a negative contour. Interestingly, a positive area is observed in the C-terminal region of the first CP module, enclosing peptide 31-45, known to be a binding site for protein S. This observation suggests that electrostatic interactions can be of importance for the interaction of C4BP to protein S. A solvent-accessible hydrophobic patch, located nearby and involving the peptide 31-45, was also found in the model, further confirming that this area is involved in the interaction with protein S. The contribution of beta-chain residues 31-45 to the affinity for protein S was studied further by means of synthetic mutant peptides. The results suggest that both electrostatic and hydrophobic interactions are important for the binding to protein S.
Villoutreix
B O
BO
VTT Biotechnology and Food Research, Espoo, Finland.
Fernández
J A
JA
Teleman
O
O
Griffin
J H
JH
D000595:Amino Acid Sequence; D001665:Binding Sites; D017242:Complement Factor H / Q000737:chemistry; D003169:Complement Inactivator Proteins; D003196:Computer Graphics; D003198:Computer Simulation; D016384:Consensus Sequence / Q000235:genetics; D006023:Glycoproteins; D006031:Glycosylation; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017293:Protein S / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011951:Receptors, Complement / Q000737:chemistry*
D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D010455:Peptides; D017293:Protein S; D011951:Receptors, Complement; D017242:Complement Factor H