Yuriev E, Ramsland P A, Edmundson A B
Crystallography Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Scand J Immunol. 2002 Mar;55(3):242-55. doi: 10.1046/j.0300-9475.2002.01032.x.
A monoclonal immunoglobulin (Ig)M cryoglobulin (Mez) with interesting binding behaviour was isolated from a Waldenström's macroglobulinemia (WM) patient. It demonstrated very strong binding to peptides derived from the sequences of human IgG. However, when tested for binding to intact IgG, this antibody (Ab) did not show any rheumatoid factor (RF) activity. We propose several nonexclusive structural interpretations of the Mez-binding propensities, based on the orientations and solvent accessibilities of ligand residues and the nature of the Ab-binding site. To further characterize the structural features of Mez-peptide binding, IgG-derived octapeptides were docked into the Mez fragment variable (Fv)-binding site, revealing additional reasons for Mez-binding selectivity based on the interactions of the docked peptides with the Mez Fv. The problem was also approached from an immunological perspective. Comparisons of Mez variable region of the light chain (VL)/variable region of the heavy chain (VH) sequences with those of human germlines and known IgM RFs allowed us to provide a possible outline tracing the structural and functional origins of the Mez IgM. Coupled with examinations of interactions in docked complexes, this analysis led us to propose that the potential for RF activity, demonstrated through Mez binding to IgG-derived peptides, was owing to the inherent sequence and structure of the Mez IgM, rather than to somatic mutations. Thus, Mez IgM may occupy an intermediate niche between IgMs with and without RF activity.
从一名华氏巨球蛋白血症（WM）患者中分离出一种具有有趣结合行为的单克隆免疫球蛋白（Ig）M冷球蛋白（Mez）。它对源自人IgG序列的肽表现出非常强的结合能力。然而，当测试其与完整IgG的结合时，这种抗体（Ab）未显示出任何类风湿因子（RF）活性。基于配体残基的取向和溶剂可及性以及Ab结合位点的性质，我们提出了几种关于Mez结合倾向的非排他性结构解释。为了进一步表征Mez - 肽结合的结构特征，将源自IgG的八肽对接至Mez片段可变区（Fv）结合位点，揭示了基于对接肽与Mez Fv相互作用的Mez结合选择性的其他原因。该问题也从免疫学角度进行了探讨。将Mez轻链可变区（VL）/重链可变区（VH）序列与人种系和已知IgM RF的序列进行比较，使我们能够勾勒出Mez IgM结构和功能起源的可能轮廓。结合对接复合物中相互作用的研究，该分析使我们提出，通过Mez与源自IgG的肽结合所显示的RF活性潜力，归因于Mez IgM的固有序列和结构，而非体细胞突变。因此，Mez IgM可能占据具有和不具有RF活性的IgM之间的中间位置。
