Crystal structure of a Staphylococcus aureus protein A domain complexed with the Fab fragment of a human IgM antibody:: Structural basis for recognition of B-cell receptors and superantigen activity
Crystal structure of a Staphylococcus aureus protein A domain complexed with the Fab fragment of a human IgM antibody:: Structural basis for recognition of B-cell receptors and superantigen activity
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DOI：
10.1073/pnas.97.10.5399
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发表时间：
2000-05-09
影响因子：
11.1
通讯作者：
Silverman, GJ
中科院分区：
文献类型：
--
作者：
Graille, M;Stura, EA;Silverman, GJ
金黄色葡萄球菌产生一种毒力因子，蛋白A（SpA），含有5个同源的免疫球蛋白结合域。SpA与膜锚定Ig的Fab区的相互作用可以刺激大部分a细胞，有助于淋巴细胞克隆选择。为了理解这种活性的分子基础，我们已经解决了SpA的结构域D和人IgM抗体的Fab片段之间的复合物的晶体结构到2.7埃分辨率。在复合物中，结构域D的螺旋II和III通过框架残基与Fab重链（V-H）的可变区相互作用，而不涉及抗原识别中涉及的高变区。接触残基在人V（H）3抗体中是高度保守的，但在其他家族中不是。来自结构域D的接触残基在所有SpA 19结合结构域中也是保守的，这表明每个结构域可以以类似的方式结合。这种相互作用的特点平行的葡萄球菌肠毒素，许多T细胞的超抗原的报告。IG V-H区和T细胞受体V-β区之间的结构同源性便于它们的比较，并且两种类型的相互作用都涉及远离抗原结合位点的淋巴细胞受体表面。然而，据报道，T细胞超抗原通过氢键与T细胞受体V-β骨架原子以一级序列独立的方式相互作用，而SpA依赖于与残基侧链的序列限制性构象结合，这表明这种常见的细菌病原体已经采用了不同的分子识别策略来影响大量的B和T淋巴细胞。
Staphylococcus aureus produces a virulence factor, protein A (SpA), that contains five homologous Ig-binding domains. The interactions of SpA with the Fab region of membrane-anchored Igs can stimulate a large fraction of a cells, contributing to lymphocyte clonal selection. To understand the molecular basis for this activity, we have solved the crystal structure of the complex between domain D of SpA and the Fab fragment of a human IgM antibody to 2.7-Angstrom resolution. In the complex, helices II and III of domain D interact with the variable region of the Fab heavy chain (V-H) through framework residues, without the involvement of the hypervariable regions implicated in antigen recognition. The contact residues are highly conserved in human V(H)3 antibodies but not in other families. The contact residues from domain D also are conserved among all SpA 19-binding domains, suggesting that each could bind in a similar manner. Features of this interaction parallel those reported for staphylococcal enterotoxins that are superantigens for many T cells. The structural homology between Ig V-H regions and the T-cell receptor V-beta regions facilitates their comparison, and both types of interactions involve lymphocyte receptor surface remote from the antigen binding site. However, T-cell superantigens reportedly interact through hydrogen bonds with T-cell receptor V-beta backbone atoms in a primary sequence-independent manner, whereas SpA relies on a sequence-restricted conformational binding with residue side chains, suggesting that this common bacterial pathogen has adopted distinct molecular recognition strategies for affecting large sets of B and T lymphocytes.