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Molecular basis of human CD22 function and therapeutic targeting

Author

Listed:
  • June Ereño-Orbea

    (The Hospital for Sick Children Research Institute)

  • Taylor Sicard

    (The Hospital for Sick Children Research Institute
    University of Toronto)

  • 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
    University of Toronto
    University of Toronto)

  • Jean-Philippe Julien

    (The Hospital for Sick Children Research Institute
    University of Toronto
    University of Toronto)

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.

Suggested Citation

  • June Ereño-Orbea & Taylor Sicard & Hong Cui & Mohammad T. Mazhab-Jafari & Samir Benlekbir & Alba Guarné & John L. Rubinstein & Jean-Philippe Julien, 2017. "Molecular basis of human CD22 function and therapeutic targeting," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00836-6
    DOI: 10.1038/s41467-017-00836-6
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