Diversity in the C3b Convertase Contact Residues and Tertiary Structures of the Staphylococcal Complement Inhibitor (SCIN) Protein Family*
Diversity in the C3b Convertase Contact Residues and Tertiary Structures of the Staphylococcal Complement Inhibitor (SCIN) Protein Family*
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葡萄球菌补体抑制剂 (SCIN) 蛋白家族的 C3b 转化酶接触残基和三级结构的多样性*
DOI：
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发表时间：
2011
影响因子：
4.8
通讯作者：
B. Geisbrecht
中科院分区：
文献类型：
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作者：
B. Garcia;B. Summers;Zhuoer Lin;K. Ramyar;Daniel Ricklin;Divya V. Kamath;Z. Fu;John D Lambris;B. Geisbrecht
背景：金黄色葡萄球菌已经进化出一系列破坏人类补体系统的机制。结果：我们报告了两种葡萄球菌补体抑制剂蛋白 SCIN-B 和 SCIN-D 的结构。结论：我们已经确定了活性 SCIN 蛋白中 C3b 识别的差异，并提出了 SCIN-D 缺乏 C3b 结合的物理基础。意义：该分析可能为未来补体靶向治疗的设计提供信息。为了在免疫能力强的宿主中生存，病原体金黄色葡萄球菌表达并分泌一系列复杂的蛋白质，抑制补体系统。其中包括葡萄球菌补体抑制剂 (SCIN)，它由三种活性蛋白（SCIN-A、-B 和 -C）和一种据称无活性的成员（SCIN-D 或 ORF-D）组成。由于之前的工作几乎完全集中于 SCIN-A，因此我们试图提供其他 SCIN 蛋白的初始结构/功能信息。为此，我们分别以 1.5 和 3.4 Å 的分辨率确定了 SCIN-B 活性 N 端截短突变体（称为 SCIN-B18-85）的晶体结构，该突变体分别游离和与补体成分 C3 的 C3c 片段结合。 C3c/SCIN-B18-85 结构与 C3c/SCIN-A 结构的比较表明，两种蛋白质都针对 C3b/C3c 表面上的相同功能热点，但在残基类型和在 C3b/C3c 界面形成的相互作用方面具有多样性。最重要的是，这些结构允许将 Arg44 和 Tyr51 鉴定为 SCIN-B 与 C3b 结合以及随后抑制 A C3 转化酶的关键残基。此外，我们还以 1.3 Å 极限分辨率解析了 SCIN-D 的几种晶体结构。这揭示了相对于 SCIN-A 和 SCIN-B 的 N 端 α 螺旋的意外结构偏差。静电势和表面互补性的比较分析提出了 SCIN-D 无法结合 C3b/C3c 的物理解释。总之，这些研究提供了对金黄色葡萄球菌免疫逃避的更全面了解，并增强了 SCIN 蛋白作为补体靶向治疗设计模板的潜在用途。
Background: Staphylococcus aureus has evolved a web of mechanisms to disrupt the human complement system. Results: We report the structures of two staphylococcal complement inhibitor proteins, SCIN-B and SCIN-D. Conclusion: We have identified differences in C3b recognition within active SCIN proteins and suggest a physical basis for lack of C3b binding by SCIN-D. Significance: This analysis may inform future design of complement-targeted therapeutics. 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 Å 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 Arg44 and Tyr51 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 Å limiting resolution. This revealed an unexpected structural deviation in the N-terminal α 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.
DOI：
10.1107/s174430910901207x
发表时间：
2009-05-01
影响因子：
0.9
作者：
Garcia, Brandon L.;Tzekou, Apostolia;Geisbrecht, Brian V.
通讯作者：
Geisbrecht, Brian V.
DOI：
10.1016/s0162-3109(00)80300-8
发表时间：
2000-08-01
期刊：
IMMUNOPHARMACOLOGY
影响因子：
--
作者：
Pangburn, MK
通讯作者：
Pangburn, MK
影响因子：
5.6
作者：
Garcia BL;Ramyar KX;Tzekou A;Ricklin D;McWhorter WJ;Lambris JD;Geisbrecht BV
通讯作者：
Geisbrecht BV