<br>人类 CD22 功能和治疗靶向的分子基础。,Nature Communications

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人类 CD22 功能和治疗靶向的分子基础。
Nature Communications ( IF 14.7 ) Pub Date : 2017-10-02 , DOI: 10.1038/s41467-017-00836-6
June Ereño-Orbea ₁ , Taylor Sicard _{1,

2} , Hong Cui ₁ , Mohammad T Mazhab-Jafari ₁ , Samir Benlekbir ₁ , Alba Guarné ₃ , John L Rubinstein _{1,

2,

4} , Jean-Philippe Julien _{1,

2,

5}

Affiliation

CD22 维持 B 细胞抑制的基线水平，以控制体液免疫。作为一种 B 细胞限制性抗原，CD22 是针对导致自身免疫性疾病和血癌的失调 B 细胞的治疗的靶点。在这里，我们以 2.1 Å 分辨率报告了人 CD22 的晶体结构，这表明 α2-6 唾液酸配体的特异性是由预先形成的 β-发夹决定的，作为唾液酸结合免疫球蛋白型凝集素的独特识别模式。 CD22 胞外域采用扩展构象，有利于 B 细胞上同时形成 CD22 纳米簇，并与反式配体结合，以避免哺乳动物发生自身免疫。我们以 3.1 Å 分辨率从结构上描绘了治疗性抗体依帕珠单抗靶向的 CD22 位点，并确定了 CD22 N 连接糖基化在抗体结合中的关键作用。我们的研究为 B 细胞抑制机制提供了分子见解，并为 B 细胞功能障碍的免疫调节剂设计提供了宝贵的线索。B 细胞特异性共受体 CD22 是消除失调 B 细胞的治疗靶点。在这里，作者对 CD22 的胞外域进行了结构表征，并展示了其与结合的治疗性抗体依帕珠单抗 (epratuzumab) 的晶体结构，从而深入了解了 B 细胞激活的抑制机制。

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Molecular basis of human CD22 function and therapeutic targeting.

CD22 maintains a baseline level of B-cell inhibition to keep humoral immunity in check. As a B-cell-restricted antigen, CD22 is targeted in therapies against dysregulated B cells that cause autoimmune diseases and blood cancers. Here we report the crystal structure of human CD22 at 2.1 Å resolution, which reveals that specificity for α2-6 sialic acid ligands is dictated by a pre-formed β-hairpin as a unique mode of recognition across sialic acid-binding immunoglobulin-type lectins. The CD22 ectodomain adopts an extended conformation that facilitates concomitant CD22 nanocluster formation on B cells and binding to trans ligands to avert autoimmunity in mammals. We structurally delineate the CD22 site targeted by the therapeutic antibody epratuzumab at 3.1 Å resolution and determine a critical role for CD22 N-linked glycosylation in antibody engagement. Our studies provide molecular insights into mechanisms governing B-cell inhibition and valuable clues for the design of immune modulators in B-cell dysfunction.The B-cell-specific co-receptor CD22 is a therapeutic target for depleting dysregulated B cells. Here the authors structurally characterize the ectodomain of CD22 and present its crystal structure with the bound therapeutic antibody epratuzumab, which gives insights into the mechanism of inhibition of B-cell activation.

更新日期：2017-10-02

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