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.
ORIGINAL RESEARCH PAPER
Ponnuraj, K. et al. A “dock, lock, and latch” structural model for a staphylococcal adhesin binding to fibrinogen. Cell 115, 217–228 (2003)
Foster, T. J. & Höök, M. et al. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 6, 484–488 (1998)
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O'Connell, D. Dock, lock and latch. Nat Rev Microbiol 1, 171 (2003). https://doi.org/10.1038/nrmicro788
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