To survive in immune-competent hosts, the pathogen Staphylococcus aureus expresses and secretes a sophisticated array of proteins that inhibit the complement system. Among these are the staphylococcal complement inhibitors (SCIN), which are composed of three active proteins (SCIN-A, -B, and -C) and one purportedly inactive member (SCIN-D or ORF-D). Because previous work has focused almost exclusively on SCIN-A, we sought to provide initial structure/function information on additional SCIN proteins. To this end we determined crystal structures of an active, N-terminal truncation mutant of SCIN-B (denoted SCIN-B18-85) both free and bound to the C3c fragment of complement component C3 at 1.5 and 3.4 angstrom resolution, respectively. Comparison of the C3c/SCIN-B18-85 structure with that of C3c/SCIN-A revealed that both proteins target the same functional hotspot on the C3b/C3c surface yet harbor diversity in both the type of residues and interactions formed at their C3b/C3c interfaces. Most importantly, these structures allowed identification of Arg(44) and Tyr(51) as residues key for SCIN-B binding to C3b and subsequent inhibition of the AP C3 convertase. In addition, we also solved several crystal structures of SCIN-D to 1.3 angstrom limiting resolution. This revealed an unexpected structural deviation in the N-terminal alpha helix relative to SCIN-A and SCIN-B. Comparative analysis of both electrostatic potentials and surface complementarity suggest a physical explanation for the inability of SCIN-D to bind C3b/C3c. Together, these studies provide a more thorough understanding of immune evasion by S. aureus and enhance potential use of SCIN proteins as templates for design of complement targeted therapeutics.
%0 Journal Article
%1 Garcia:2012in
%A Garcia, Brandon L.
%A Summers, Brady J.
%A Lin, Zhuoer
%A Ramyar, Kasra X.
%A Ricklin, Daniel
%A Kamath, Divya V.
%A Fu, Zheng-Qing
%A Lambris, John D.
%A Geisbrecht, Brian V.
%D 2012
%J Journal of Biological Chemistry
%K imported
%N 1
%P 628--640
%R 10.1074/jbc.M111.298984
%T Diversity in the C3b Convertase Contact Residues and Tertiary Structures of the Staphylococcal Complement Inhibitor (SCIN) Protein Family
%U http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=22086928&retmode=ref&cmd=prlinks
%V 287
%X To survive in immune-competent hosts, the pathogen Staphylococcus aureus expresses and secretes a sophisticated array of proteins that inhibit the complement system. Among these are the staphylococcal complement inhibitors (SCIN), which are composed of three active proteins (SCIN-A, -B, and -C) and one purportedly inactive member (SCIN-D or ORF-D). Because previous work has focused almost exclusively on SCIN-A, we sought to provide initial structure/function information on additional SCIN proteins. To this end we determined crystal structures of an active, N-terminal truncation mutant of SCIN-B (denoted SCIN-B18-85) both free and bound to the C3c fragment of complement component C3 at 1.5 and 3.4 angstrom resolution, respectively. Comparison of the C3c/SCIN-B18-85 structure with that of C3c/SCIN-A revealed that both proteins target the same functional hotspot on the C3b/C3c surface yet harbor diversity in both the type of residues and interactions formed at their C3b/C3c interfaces. Most importantly, these structures allowed identification of Arg(44) and Tyr(51) as residues key for SCIN-B binding to C3b and subsequent inhibition of the AP C3 convertase. In addition, we also solved several crystal structures of SCIN-D to 1.3 angstrom limiting resolution. This revealed an unexpected structural deviation in the N-terminal alpha helix relative to SCIN-A and SCIN-B. Comparative analysis of both electrostatic potentials and surface complementarity suggest a physical explanation for the inability of SCIN-D to bind C3b/C3c. Together, these studies provide a more thorough understanding of immune evasion by S. aureus and enhance potential use of SCIN proteins as templates for design of complement targeted therapeutics.
@article{Garcia:2012in,
abstract = {To survive in immune-competent hosts, the pathogen Staphylococcus aureus expresses and secretes a sophisticated array of proteins that inhibit the complement system. Among these are the staphylococcal complement inhibitors (SCIN), which are composed of three active proteins (SCIN-A, -B, and -C) and one purportedly inactive member (SCIN-D or ORF-D). Because previous work has focused almost exclusively on SCIN-A, we sought to provide initial structure/function information on additional SCIN proteins. To this end we determined crystal structures of an active, N-terminal truncation mutant of SCIN-B (denoted SCIN-B18-85) both free and bound to the C3c fragment of complement component C3 at 1.5 and 3.4 angstrom resolution, respectively. Comparison of the C3c/SCIN-B18-85 structure with that of C3c/SCIN-A revealed that both proteins target the same functional hotspot on the C3b/C3c surface yet harbor diversity in both the type of residues and interactions formed at their C3b/C3c interfaces. Most importantly, these structures allowed identification of Arg(44) and Tyr(51) as residues key for SCIN-B binding to C3b and subsequent inhibition of the AP C3 convertase. In addition, we also solved several crystal structures of SCIN-D to 1.3 angstrom limiting resolution. This revealed an unexpected structural deviation in the N-terminal alpha helix relative to SCIN-A and SCIN-B. Comparative analysis of both electrostatic potentials and surface complementarity suggest a physical explanation for the inability of SCIN-D to bind C3b/C3c. Together, these studies provide a more thorough understanding of immune evasion by S. aureus and enhance potential use of SCIN proteins as templates for design of complement targeted therapeutics.},
added-at = {2017-12-08T05:18:19.000+0100},
affiliation = {Univ Missouri, Sch Biol Sci, Div Cell Biol {\&} Biophys, Kansas City, MO 64110 USA},
author = {Garcia, Brandon L. and Summers, Brady J. and Lin, Zhuoer and Ramyar, Kasra X. and Ricklin, Daniel and Kamath, Divya V. and Fu, Zheng-Qing and Lambris, John D. and Geisbrecht, Brian V.},
biburl = {https://www.bibsonomy.org/bibtex/24026ad7814c80bac8a597d972e9e5a4e/lambris},
date-added = {2012-03-27T20:48:57GMT},
date-modified = {2017-12-08T04:17:02GMT},
doi = {10.1074/jbc.M111.298984},
interhash = {fc9fa3798e08a739f4468afd74966bab},
intrahash = {4026ad7814c80bac8a597d972e9e5a4e},
journal = {Journal of Biological Chemistry},
keywords = {imported},
language = {English},
number = 1,
pages = {628--640},
pmcid = {PMC3249117},
pmid = {22086928},
rating = {0},
timestamp = {2017-12-08T05:18:19.000+0100},
title = {{Diversity in the C3b Convertase Contact Residues and Tertiary Structures of the Staphylococcal Complement Inhibitor (SCIN) Protein Family}},
uri = {\url{papers3://publication/doi/10.1074/jbc.M111.298984}},
url = {http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=22086928&retmode=ref&cmd=prlinks},
volume = 287,
year = 2012
}