Abstract
The fibrinogen (Fg) binding MSCRAMM Clumping factor A (ClfA) from Staphylococcus aureus interacts with the C-terminal region of the fibrinogen (Fg) γ-chain. ClfA is the major virulence factor responsible for the observed clumping of S. aureus in blood plasma and has been implicated as a virulence factor in a mouse model of septic arthritis and in rabbit and rat models of infective endocarditis. We report here a high-resolution crystal structure of the ClfA ligand binding segment in complex with a synthetic peptide mimicking the binding site in Fg. The residues in Fg required for binding to ClfA are identified from this structure and from complementing biochemical studies. Furthermore, the platelet integrin αIIbβ3 and ClfA bind to the same segment in the Fg γ-chain but the two cellular binding proteins recognize different residues in the common targeted Fg segment. Based on these differences, we have identified peptides that selectively antagonize the ClfA-Fg interaction. The ClfA-Fg binding mechanism is a variant of the “Dock, Lock and Latch” mechanism previously described for the Staphylococcus epidermidis SdrG–Fg interaction. The structural insights gained from analyzing the ClfANFg peptide complex and identifications of peptides that selectively recognize ClfA but not αIIbβ3 may allow the design of novel anti-staphylococcal agents. Our results also suggest that different MSCRAMMs with similar structural organization may have originated from a common ancestor but have evolved to accommodate specific ligand structures.
Highlights
Staphylococcus aureus is a Gram-positive commensal organism that permanently colonizes 20% of healthy adults and transiently colonizes up to 50% of the general population [1]
Despite the fact that the two proteins bind at the same region, the mode of recognition is significantly different. Exploiting this difference in recognition, we have demonstrated that agents could be designed that inhibit the clumping factor A (ClfA)–Fg interaction but do not interfere with the interaction of Fg with the platelet integrin
These results demonstrate that an open conformation may not be required for Fg binding to ClfA and that Fg binding by ClfA involves a mechanism that is different from the DLL mechanism employed by SdrG
Summary
Staphylococcus aureus is a Gram-positive commensal organism that permanently colonizes 20% of healthy adults and transiently colonizes up to 50% of the general population [1]. Within the last decade a dramatic increase in the number of invasive infections caused by community-acquired S. aureus have been recorded in otherwise healthy children and young adults [3,4]. This outbreak together with the continued increase in antibiotic resistance among clinical strains underscores the need for new prevention and treatment strategies [1]. ClfA is the major staphylococcal fibrinogen (Fg) binding protein and is responsible for the observed clumping of S. aureus in blood plasma [9,10].
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