title: Binding of the human complement regulators CFHR1 and factor H by streptococcal collagen-like protein 1 (Scl1) via their conserved C termini allows control of the complement cascade at multiple levels.
abstract: Group A streptococci (GAS) utilize soluble human complement regulators to evade host complement attack. Here, we characterized the binding of the terminal complement complex inhibitor complement Factor H-related protein 1 (CFHR1) and of the C3 convertase regulator Factor H to the streptococcal collagen-like proteins (Scl). CFHR1 and Factor H, but no other member of the Factor H protein family (CFHR2, CFHR3, or CFHR4A), bound to the two streptococcal proteins Scl1.6 and Scl1.55, which are expressed by GAS serotypes M6 and M55. The two human regulators bound to the Scl1 proteins via their conserved C-terminal attachment region, i.e. CFHR1 short consensus repeats 3-5 (SCR3-5) and Factor H SCR18-20. Binding was affected by ionic strength and by heparin. CFHR1 and the C-terminal attachment region of Factor H did not bind to Scl1.1 and Scl2.28 proteins but did bind to intact M1-type and M28-type GAS, which express Scl1.1 and Scl2.28, respectively, thus arguing for the presence of an additional binding mechanism to CFHR1 and Factor H. Furthermore mutations within the C-terminal heparin-binding region and Factor H mutations that are associated with the acute renal disease atypical hemolytic uremic syndrome blocked the interaction with the two streptococcal proteins. Binding of CFHR1 affected the complement regulatory functions of Factor H on the level of the C3 convertase. Apparently, streptococci utilize two types of complement regulator-acquiring surface proteins; type A proteins, as represented by Scl1.6 and Scl1.55, bind to CFHR1 and Factor H via their conserved C-terminal region and do not bind the Factor H-like protein 1 (FHL-1). On the contrary, type B proteins, represented by M-, M-like, and the fibronectin-binding protein Fba proteins, bind Factor H and FHL-1 via domain SCR7 and do not bind CFHR1. In conclusion, binding of CFHR1 is at the expense of Factor H-mediated regulatory function at the level of C3 convertase and at the gain of a regulator that controls complement at the level of the C5 convertase and formation of the terminal complement complex.
authors.affiliation: Department of Infection Biology, Hans Knoell Institute, 07745 Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Reuter
authors.forename: Clayton C
authors.initials: CC
authors.lastname: Caswell
authors.forename: Slawomir
authors.initials: S
authors.lastname: Lukomski
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
mesh_terms: D000208:Acute Disease; D065766:Atypical Hemolytic Uremic Syndrome; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D003167:Complement Activation; D050577:Complement C3-C5 Convertases / Q000235:genetics / Q000378:metabolism; D003180:Complement C3b Inactivator Proteins / Q000235:genetics / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism*; D015938:Complement Membrane Attack Complex / Q000235:genetics / Q000378:metabolism; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013290:Streptococcal Infections / Q000235:genetics / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D015938:Complement Membrane Attack Complex; C423454:Scl1 protein, Streptococcus; C423453:Scl2 protein, Streptococcus; D017242:Complement Factor H; D003094:Collagen; D050577:Complement C3-C5 Convertases