A structural model of the Staphylococcus aureus ClfA-fibrinogen interaction opens new avenues for the design of anti-staphylococcal therapeutics.
The fibrinogen (Fg) binding MSCRAMM Clumping factor A (ClfA) from Staphylococcus aureus interacts with the C-terminal region of the fibrinogen (Fg) gamma-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 alpha(IIb)beta(3) and ClfA bind to the same segment in the Fg gamma-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 alpha(IIb)beta(3) 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.
Ganesh
Vannakambadi K
VK
Center for Extracellular Matrix Biology, Institute of Biosciences and Technology, Texas A & M University Health Science Center, Houston, Texas, USA.
Rivera
Jose J
JJ
Smeds
Emanuel
E
Ko
Ya-Ping
YP
Bowden
M Gabriela
MG
Wann
Elisabeth R
ER
Gurusiddappa
Shivasankarappa
S
Fitzgerald
J Ross
JR
Höök
Magnus
M
D001665:Binding Sites; D003030:Coagulase / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015195:Drug Design; D005340:Fibrinogen / Q000378:metabolism*; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus
C515944:ClfA protein, Staphylococcus aureus; D003030:Coagulase; D010455:Peptides; D005340:Fibrinogen