Although the S. aureus and human proteins have unrelated amino acid sequences, secondary structure composition, and cation requirements for effective ligand binding, both proteins bind at multiple sites within one collagen molecule, with the sites in collagen varying in their affinity for the adherence molecule. We propose that (i) these evolutionarily dissimilar adherence proteins recognize collagen via similar mechanisms, (ii) the multisite, multiclass protein/ligand interactions observed in these two systems result from a binding-site trench, and (iii) this unusual binding mechanism may be thematic for proteins binding extended, rigid ligands that contain repeating structural motifs.Collagen polypeptides are largely composed of repeats of the GPX tripeptide and associate to form triple-helical monomers. These monomers combine into macroscopic fibers. Prokaryotic and eukaryotic cells bind collagen via receptors on their cell surfaces (1-6). We now hypothesize that to accommodate such an unusually shaped ligand, the collagen-binding surface proteins of these cells must adopt an atypical binding-site structure.Bacterial pathogens utilize this interaction as a means of adherence to collagenous host tissues. Some Staphylococcus aureus strains express an adhesin, Cna, 1 of the MSCRAMM class that binds collagen (1, 7-13). Cna from S. aureus FDA 574 is depicted in Fig. 1a: it contains two major domains, A and B, in addition to features characteristic of cell-surface proteins on Gram-positive bacteria (11). The collagen-binding site has been localized within the Cna A domain (12). Binding analyses demonstrate that (i) a synthetic peptide mimicking a short sequence of the A domain can inhibit collagen binding to S. aureus (8); (ii) the A domain/collagen interaction involves more than one affinity class and multiple sites of contact within a single collagen molecule (8, 10); and (iii) the B domain does not alter the collagen binding ability of the A domain (13).The crystal structure of a truncated form of the Cna A domain reveals a binding-site "trench" on one face of the protein. In molecular modeling studies, this trench was found to accommodate a triple-helical peptide that mimics the collagen structure. Symersky et al. (7) noted that this trench complemented well the structure of a collagen triple helix and binding studies of site-specific mutants of the S. aureus Cna truncate revealed that (i) no single residue or area within the trench was responsible for collagen binding, but rather, a number of contacts contributed to the protein/collagen interaction and (ii) this binding-domain truncate bound to multiple sites along a collagen molecule. The affinity of Cna for an individual site within collagen may be the consequence of the number of "good" and "bad" contacts within the binding trench.Binding of eukaryotic cells to collagen serves not only as a mechanism of tissue adherence, but also may induce a complex signaling cascade in the cell. Attachment of eukaryotic cells to the extracellular matrix is primarily medi...
