Ereño-Orbea June, Sicard Taylor, Cui Hong, Mazhab-Jafari Mohammad T, Benlekbir Samir, Guarné Alba, Rubinstein John L, Julien Jean-Philippe
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada, M5G 0A4.
Department of Biochemistry, University of Toronto, Toronto, ON, Canada, M5S 1A8.
Nat Commun. 2017 Oct 2;8(1):764. doi: 10.1038/s41467-017-00836-6.
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.
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细胞的治疗靶点。在此，我们报告了分辨率为2.1Å的人CD22晶体结构，该结构揭示了对α2-6唾液酸配体的特异性是由一个预先形成的β发夹决定的，这是唾液酸结合免疫球蛋白型凝集素独特的识别模式。CD22胞外域采用延伸构象，这有利于在B细胞上同时形成CD22纳米簇并与反式配体结合，从而避免哺乳动物中的自身免疫。我们以3.1Å的分辨率在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。我们的研究为控制B细胞抑制的机制提供了分子见解，并为B细胞功能障碍中免疫调节剂的设计提供了有价值的线索。B细胞特异性共受体CD22是清除失调B细胞的治疗靶点。在此，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的晶体结构，这为B细胞激活的抑制机制提供了见解。
