Crystal structure of a human autoimmune complex between IgM rheumatoid factor RF61 and lgG1 Fc reveals a novel epitope and evidence for affinity maturation
Crystal structure of a human autoimmune complex between IgM rheumatoid factor RF61 and lgG1 Fc reveals a novel epitope and evidence for affinity maturation
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DOI：
10.1016/j.jmb.2007.02.085
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发表时间：
2007-05-18
影响因子：
5.6
通讯作者：
Taussig, Michael J.
中科院分区：
文献类型：
--
作者：
Duquerroy, Stephane;Stura, Enrico A.;Taussig, Michael J.
类风湿因子（RF）是识别免疫球蛋白（IG）G Fc区抗原决定簇的自身抗体，与类风湿关节炎（RA）的临床严重程度相关。在这里，我们报告的X-射线晶体结构，在3埃分辨率，之间的复合物的Fc区的人IgG 1和Fab片段的单克隆IgM RF（RF 61），来自RA患者和IgG Fc具有相对较高的亲和力。在复合物中，两个Fab片段在接近C末端的表位处结合至每个Fc，并且每个表位包含来自两个C γ 3结构域的残基。Arg 355的侧链在异常亲水性表位中起着中心作用，这是RF 61的亚类特异性的原因，RF 61优先识别IgG 1、IgG 2和IgG 3，而IgG 4中相应的残基是Gln 355。与先前确定的低亲和力RF（RF-AN）与IgG 4 Fc结合的复合物（其中仅抗体结合位点最边缘的残基参与结合）相比，RF 61结合的表位以经典方式集中在V-H：V-L β-桶的轴上。互补决定区-H3环起关键作用，形成一个口袋，其中Arg 355由两个盐桥结合。抗体接触还涉及两个体细胞突变的V-H残基，加强了在产生这种RF自身抗体期间抗原驱动的IgG Fc成熟和选择过程的建议。(C)2007爱思唯尔有限公司保留所有权利。
Rheumatoid factors (RF) are autoantibodies that recognize epitopes in the Fc region of im-munoglobulin (Ig) G and that correlate with the clinical severity of rheumatoid arthritis (RA). Here we report the X-ray crystallographic structure, at 3 angstrom resolution, of a complex between the Fc region of human IgG1 and the Fab fragment of a monoclonal IgM RF (RF61), derived from an RA patient and with a relatively high affinity for IgG Fc. In the complex, two Fab fragments bind to each Fc at epitopes close to the C terminus, and each epitope comprises residues from both C gamma 3 domains. A central role in the unusually hydrophilic epitope is played by the side-chain of Arg355, accounting for the subclass specificity of RF61, which recognizes IgG1,-2, and -3 in preference to IgG4, in which the corresponding residue is Gln355. Compared with a previously determined complex of a lower affinity RF (RF-AN) bound to IgG4 Fc, in which only residues at the very edge of the antibody combining site were involved in binding, the epitope bound by RF61 is centered in classic fashion on the axis of the V-H:V-L beta-barrel. The complementarity determining region-H3 loop plays a key role, forming a pocket in which Arg355 is bound by two salt-bridges. The antibody contacts also involve two somatically mutated V-H residues, reinforcing the suggestion of a process of antigen-driven maturation and selection for IgG Fc during the generation of this RF autoantibody. (C) 2007 Elsevier Ltd. All rights reserved.