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首页> 外文期刊>Journal of Molecular Biology >Inhibitory and blocking monoclonal antibody epitopes on merozoite surface protein 1 of the malaria parasite Plasmodium falciparum
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Inhibitory and blocking monoclonal antibody epitopes on merozoite surface protein 1 of the malaria parasite Plasmodium falciparum

机译：疟原虫恶性疟原虫裂殖子表面蛋白1上的抑制性和封闭性单克隆抗体表位

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Merozoite surface protein 1 (MSP-1) is a precursor to major antigens on the surface of Plasmodium spp. merozoites, which are involved in erythrocyte binding and invasion. MSP-1 is initially processed into smaller fragments; and at the time of erythrocyte invasion one of these of 42 kDa (MSP-1(42)) is subjected to a second processing, producing 33 kDa and 19 kDa fragments (MSP-1(33) and MSP-1(19)). Certain MSP-1-specific monoclonal antibodies (mAbs) react with conformational epitopes contained within the two epidermal growth factor domains that comprise MSP-1(19), and are classified as either inhibitory (inhibit processing of MSP-1(42) and erythrocyte invasion), blocking (block the binding and function of the inhibitory mAb), or neutral (neither inhibitory nor blocking). We have mapped the epitopes for inhibitory mAbs 12.8 and 12.10, and blocking mAbs such as 1E1 and 7.5 by using site-directed mutagenesis to change specific amino acid residues in MSP-1(19) and abolish antibody binding, and by using PEPSCAN to measure the reaction of the antibodies with every octapeptide within MSP-1(42). Twenty-six individual amino acid residue changes were made and the effect of each on the binding of mAbs was assessed by Western blotting and BIAcore analysis. Individual changes had either no effect, or reduced, or completely abolished the binding of individual mAbs. No two antibodies had an identical pattern of reactivity with the modified proteins. Using PEPSCAN each mAb reacted with a number of octapeptides, most of which were derived from within the first epidermal growth factor domain, although 1E1 also reacted with peptides spanning the processing site. When the single amino acid changes and the reactive peptides were mapped onto the three-dimensional structure of MSP-1(19), it was apparent that the epitopes for the mAbs could be defined more fully by using a combination of both mutagenesis and PEPSCAN than by either method alone, and differences in the fine specificity of binding for all the different antibodies could be distinguished. The incorporation of several specific amino acid changes enabled the design of proteins that bound inhibitory but not blocking antibodies. These may be suitable for the development of MSP-1-based vaccines against malaria. (C) 2001 Academic Press. [References: 28]
机译：裂殖子表面蛋白1（MSP-1）是疟原虫属物种表面主要抗原的前体。裂殖子，与红细胞结合和入侵有关。 MSP-1首先被处理成较小的片段;在红细胞入侵时，对42 kDa（MSP-1（42））中的一个进行第二次处理，产生33 kDa和19 kDa片段（MSP-1（33）和MSP-1（19）） 。某些MSP-1特异性单克隆抗体（mAb）与包含MSP-1（19）的两个表皮生长因子域中包含的构象表位反应，并被分类为抑制性（抑制MSP-1（42）加工和红细胞加工）入侵），阻断（阻断抑制性mAb的结合和功能）或中性（既不抑制也不阻断）。我们已通过使用定点诱变来改变MSP-1（19）中的特定氨基酸残基并消除抗体结合，并通过使用PEPSCAN来测定抑制性单克隆抗体12.8和12.10的表位，并阻断单克隆抗体如1E1和7.5。抗体与MSP-1（42）中每个八肽的反应。进行了26个单独的氨基酸残基改变，并通过Western印迹和BIAcore分析评估了每种对mAb结合的影响。单个变化没有影响，或减少或完全取消了单个mAb的结合。没有两种抗体与修饰的蛋白质具有相同的反应模式。使用PEPSCAN，每个mAb与许多八肽反应，尽管其中1E1也与跨越加工位点的肽反应，但大多数八肽都来自第一个表皮生长因子域。当单个氨基酸变化并将反应性肽定位到MSP-1（19）的三维结构上时，很明显，通过结合诱变和PEPSCAN，可以更充分地定义mAb的表位。仅通过这两种方法，就可以区分所有不同抗体的结合特异性差异。几个特定氨基酸变化的结合使得能够设计结合抑制性但不阻断抗体的蛋白质。这些可能适合开发基于MSP-1的抗疟疾疫苗。 （C）2001学术出版社。 [参考：28]

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