Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor.
Activation of the complement system generates potent chemoattractants and leads to the opsonization of cells for immune clearance. Short-lived protease complexes cleave complement component C3 into anaphylatoxin C3a and opsonin C3b. Here we report the crystal structure of the C3 convertase formed by C3b and the protease fragment Bb, which was stabilized by the bacterial immune-evasion protein SCIN. The data suggest that the proteolytic specificity and activity depend on the formation of dimers of C3 with C3b of the convertase. SCIN blocked the formation of a productive enzyme-substrate complex. Irreversible dissociation of the complex of C3b and Bb is crucial to complement regulation and was determined by slow binding kinetics of the Mg(2+)-adhesion site in Bb. Understanding the mechanistic basis of the central complement-activation step and microbial immune evasion strategies targeting this step will aid in the development of complement therapeutics.
Rooijakkers
Suzan H M
SH
Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Wu
Jin
J
Ruyken
Maartje
M
van Domselaar
Robert
R
Planken
Karel L
KL
Tzekou
Apostolia
A
Ricklin
Daniel
D
Lambris
John D
JD
Janssen
Bert J C
BJ
van Strijp
Jos A G
JA
Gros
Piet
P
D001426:Bacterial Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D003176:Complement C3 / Q000737:chemistry / Q000378:metabolism; D051561:Complement C3 Convertase, Alternative Pathway / Q000737:chemistry* / Q000378:metabolism; D050577:Complement C3-C5 Convertases / Q000737:chemistry / Q000378:metabolism; D003179:Complement C3b / Q000737:chemistry / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000276:immunology; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance
D001426:Bacterial Proteins; D003176:Complement C3; D003169:Complement Inactivator Proteins; D003179:Complement C3b; D050577:Complement C3-C5 Convertases; D051561:Complement C3 Convertase, Alternative Pathway