Molecular basis of human CD22 function and therapeutic targeting

June Ereño-Orbea, Taylor Sicard, Hong Cui, Mohammad T. Mazhab-Jafari, Samir Benlekbir, Alba Guarné, John L. Rubinstein and Jean-Philippe Julien ()
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June Ereño-Orbea: The Hospital for Sick Children Research Institute
Taylor Sicard: The Hospital for Sick Children Research Institute
Hong Cui: The Hospital for Sick Children Research Institute
Mohammad T. Mazhab-Jafari: The Hospital for Sick Children Research Institute
Samir Benlekbir: The Hospital for Sick Children Research Institute
Alba Guarné: McMaster University
John L. Rubinstein: The Hospital for Sick Children Research Institute
Jean-Philippe Julien: The Hospital for Sick Children Research Institute

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00836-6

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