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首页> 外文期刊>Biochemistry >Localization of a conformational epitope common to non-native and fibrillar immunoglobulin light chains.
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Localization of a conformational epitope common to non-native and fibrillar immunoglobulin light chains.

机译：非天然和纤维状免疫球蛋白轻链常见的构象表位的定位。

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Amyloid fibrils and partially unfolded intermediates may be distinguished serologically from native amyloidogenic precursor proteins or peptides. In this regard, we had previously reported that the IgG1 mAb 11-1F4, generated by immunizing mice with a thermally denatured variable region fragment of the human Igkappa4 Bence Jones protein Len, reacted specifically with light chain (LC) fibrils, irrespective of kappa or lambda isotype but, notably, did not with native molecules (Hrncic, R. et al. (2000) Am. J. Pathol. 157, 1239-1246). To elucidate the molecular basis of this specificity, we have used a europium-linked fluorescent immunoassay, where it was demonstrated through epitope mapping that mAb 11-1F4 recognizes a conformational determinant contained within the first (N-terminal) 18 amino acids of misfolded LCs. The nature of this epitope was evidenced in competition studies where the peptide Len (1-18), but not the intact protein or other LCs, inhibited the binding of the antibody to fibrils. This unique reactivity was dependent on the structural integrity of this portion of the molecule, particularly the presence of a highly conserved prolyl residue at position 8. On the basis of our experimental data, we posit that the mAb 11-1F4 binding site found on partially denatured and fibrillar LCs involves an inducible N-terminal main chain reversal that results in the formation of a proline anchored beta-turn. Our delineation of this LC fibril-associated epitope provides the rationale for the design of novel amyloid-reactive antibodies with diagnostic and therapeutic potential for patients with LC-associated and other forms of amyloidosis.
机译：淀粉样蛋白原纤维和部分展开的中间体可以从天然淀粉样蛋白前体蛋白或肽血晶碱进行区分。在这方面，我们先前据报道，通过用Hym Igkappa4衡量琼松蛋白Len的热变性可变区片段免疫小鼠产生的IgG1 mAb 11-1F4，特别是用轻链（LC）原纤维，无论κ还是kapp Lambda同种型，特别是，没有用本土分子（Hrncic，R.等人。（2000）am。J.Povol。157,1239-1246）。为了阐明这种特异性的分子基础，我们使用了铕连接的荧光免疫测定，通过表位映射来证明MAB 11-1F4识别出在错误折叠的LCS的第一（N-末端）18氨基酸内含有的构象的决定因素。在竞争研究中证明了该表位的性质，其中肽LEN（1-18）但不是完整的蛋白质或其他LCS，抑制抗体对原纤维的结合。这种独特的反应性取决于该部分分子的结构完整性，特别是在第8位的基础上存在高度保守的脯氨酰残基的存在。在我们的实验数据的基础上，我们将MAB 11-1F4结合位点分开变性和纤维状LCs涉及诱导的N-末端主链逆转，导致脯氨酸锚定β-转弯。我们对该LC母纤维相关表位的描绘提供了具有LC相关和其他形式的淀粉样蛋白症的患者的诊断和治疗潜力的新型淀粉样蛋白反应抗体的基本原理。

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