SdrG interacting with a peptide that corresponds to its binding site in the human fibrinogen β-chain (residues 6-20; in purple). Courtesy of Sthanam Narayana, University of Alabama at Birmingham, USA.

The attachment of microorganisms to host tissue represents a first crucial step in most bacterial infections and involves direct interaction between a bacterial surface adhesin and a host ligand. For extracellular pathogens like Staphylococcus epidermidis, frequently exposed to the high fluid shear forces present in the bloodstream, a strong, robust interaction is required to initate colonization and ultimately infection. Reporting in Cell, Sthanam Narayana, Magnus Höök and colleagues have elucidated the molecular basis for one such interaction — between a cell-wall-anchored protein from S. epidermidis (SdrG) and the host protein, fibrinogen — and propose a general mode of ligand binding for related adhesins in Gram-positive bacteria.

SdrG is one of a family of bacterial surface proteins that mediate interaction with the host extracellular matrix. Known as MSCRAMMS (microbial surface components recognizing adhesive matrix molecules), this family of adhesins have a similar modular design and an IgG-like folded domain organization, and are implicated as being important for microbial virulence. Ponnuraj et al. solved the structure of the ligand-binding domain of SdrG, both as an apoprotein, and in complex with a synthetic peptide analagous to the binding site in its ligand, fibrinogen. They further investigated the binding mechanism using site-directed mutagenesis, truncation mutagensis and peptide amino acid replacement. Analysis of the structure revealed that the SdrG protein has an open conformation that allows access of the ligand to a binding cleft. Following binding of the ligand, a structural rearrangement is induced at the C-terminus of the protein such that access to and from the binding cleft is blocked, and the 'docked' peptide is 'locked' in place. To stabilize the structure, the rearranged C-terminal β-sheet inserts between two β-sheets in an adjacent domain, 'latching' the protein-ligand complex together. Investigation of the interaction using mutant proteins and peptides provided strong support for this multi-step model of microbial adhesion.

The Höök and Narayana groups have also recently solved the structures of the ligand-binding domain of fibrinogen-binding MSCRAMMS from Staphylococcus aureus. Investigation of these data in conjunction with a survey of the available genomes of other pathogenic Gram-positive bacteria, revealed the presence of key features of the dock, lock and latch mechanism in a wide variety of MSCRAMM candidates. These anaylses suggest that this interaction mechanism is likely to represent a general mode of ligand-binding in this group of related adhesins from Gram-positive bacteria.