期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 283, 期 32, 页码 22113-22120出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M802636200
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资金
- Biotechnology and Biological Sciences Research Council [BBS/B/12121] Funding Source: Medline
- Medical Research Council [MC_U117533887] Funding Source: Medline
- Wellcome Trust [076124] Funding Source: Medline
- MRC [MC_U117533887] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/B/12121] Funding Source: researchfish
- Medical Research Council [MC_U117533887] Funding Source: researchfish
Among the recently discovered Staphylococcus aureus immune evasion proteins, Sbi is unique in its ability to interact with components of both the adaptive and innate immune systems of the host. Sbi domains I and II (Sbi-I and Sbi-II) bind IgG. Sbi domain IV (residues 198 - 266) binds the central complement protein C3. When linked to Sbi-III, Sbi-IV induces a futile consumption of complement via alternative pathway activation, whereas isolated Sbi-IV specifically inhibits the alternative pathway without complement consumption. Here we have determined the three- dimensional structure of Sbi-IV by NMR spectroscopy, showing that Sbi-IV adopts a three- helix bundle fold similar to those of the S. aureus complement inhibitors Efb-C, Ehp, and SCIN. The H-1-N-15 HSQC spectrum of Sbi-III indicates that this domain, essential for futile complement consumption, is natively unfolded, at least when isolated from the rest of Sbi. Sbi-IV and Sbi-III-IV both bind C3dg with 1: 1 stoichiometry and submicromolar affinity. Despite low overall sequence identity, Sbi possesses the same residues as Efb at two positions essential for Efb-C binding to C3d. Mutation to alanine of either of these residues, Arg-231 and Asn-238, abolishes both Sbi-IV binding to C3dg and Sbi-IV alternative pathway inhibition. The almost complete conservation of Sbi-III and Sbi-IV amino acid sequences across more than 30 strains isolated from human and animal hosts indicates that the unique mechanism of Sbi in complement system subversion is a feature of infections of both humans and economically important animals.
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