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含LILRB1抗体与疟原虫RIFIN结合的结构获解析
2021-04-02 21:10

瑞士大学 Antonio Lanzavecchia小组的最新研究揭示了包含LILRB1抗体与疟原虫重复散布多肽家族(RIFINs)结合的结构基础。这一研究成果在线发表在2021年3月31日出版的国际学术期刊《自然》上。

研究人员通过筛选结合LILRB1的抗体来解释RIFIN与LAIR1结合的一般意义,LILRB1是另一种抑制性受体,通过其顶端结构域与β2微球蛋白和RIFINs结合。通过对马里一个供体队提供的血浆进行筛选,研究人员鉴定了含有LILRB1抗体的个体。从三个供体分离的B细胞克隆中发现其开关区结构域含有大DNA的插入,该区域在可变–恒定(VH–CH1)弯头中编码非顶端的LILRB1细胞外结构域3和4(D3D4)或D3。

通过质谱和结合测定,研究人员发现了与LILRB1 D3结合的大量RIFIN。RIFIN与LILRB1 D3D4或含D3D4抗体Fab的复合物晶体和冷冻电镜结构揭示了RIFIN–LILRB1 D3相互作用的模式,类似于RIFIN–LAIR1。Fab具有一种非典型的三角形结构,其中LILRB1结构域的插入打开了VH–CH1的肘部结构,而不会影响VH–VL或CH1–CL的配对。

总的来说,这些发现表明RIFINs通过D3与LILRB1结合,并以自然选择的例子说明了通过将受体结构域插入VH–CH1肘部来产生新型抗体的一般原理。

据介绍,一些恶性疟原虫的RIFINs(在感染个体红细胞上表达的变异表面抗原)与抑制受体LAIR1结合,将编码LAIR1的DNA插入免疫球蛋白基因中会产生RIFIN特异性抗体。

附:英文原文

Title: Structural basis of malaria RIFIN binding by LILRB1-containing antibodies

Author: Yiwei Chen, Kai Xu, Luca Piccoli, Mathilde Foglierini, Joshua Tan, Wenjie Jin, Jason Gorman, Yaroslav Tsybovsky, Baoshan Zhang, Boubacar Traore, Chiara Silacci-Fregni, Claudia Daubenberger, Peter D. Crompton, Roger Geiger, Federica Sallusto, Peter D. Kwong, Antonio Lanzavecchia

Issue&Volume: 2021-03-31

Abstract: Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)—variant surface antigens that are expressed on infected erythrocytes1—bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies2,3. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to β2 microglobulin and RIFINs through their apical domains4,5. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable–constant (VH–CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN–LILRB1 D3 interaction that is similar to that of RIFIN–LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH–CH1 elbow without affecting VH–VL or CH1–CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH–CH1 elbow.

DOI: 10.1038/s41586-021-03378-6

Source: https://www.nature.com/articles/s41586-021-03378-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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