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Title: Molecular basis of human CD22 function and therapeutic targeting

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.

Authors:
 [1];  [2];  [1];  [1];  [1];  [3];  [2];  [2]
  1. The Hospital for Sick Children Research Inst., Toronto, ON (Canada)
  2. The Hospital for Sick Children Research Inst., Toronto, ON (Canada); Univ. of Toronto, ON (Canada)
  3. McMaster Univ., Hamilton, ON (Canada)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division; Canadian Inst. of Health Research
OSTI Identifier:
1432854
Grant/Contract Number:  
[AC02-06CH11357; PJT-148811]
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
[ Journal Volume: 8; Journal Issue: 1]; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Electron microscopy; Immunology; SAXS; X-ray crystallography

Citation Formats

Ereño-Orbea, June, Sicard, Taylor, Cui, Hong, Mazhab-Jafari, Mohammad T., Benlekbir, Samir, Guarné, Alba, Rubinstein, John L., and Julien, Jean-Philippe. Molecular basis of human CD22 function and therapeutic targeting. United States: N. p., 2017. Web. doi:10.1038/s41467-017-00836-6.
Ereño-Orbea, June, Sicard, Taylor, Cui, Hong, Mazhab-Jafari, Mohammad T., Benlekbir, Samir, Guarné, Alba, Rubinstein, John L., & Julien, Jean-Philippe. Molecular basis of human CD22 function and therapeutic targeting. United States. doi:10.1038/s41467-017-00836-6.
Ereño-Orbea, June, Sicard, Taylor, Cui, Hong, Mazhab-Jafari, Mohammad T., Benlekbir, Samir, Guarné, Alba, Rubinstein, John L., and Julien, Jean-Philippe. Mon . "Molecular basis of human CD22 function and therapeutic targeting". United States. doi:10.1038/s41467-017-00836-6. https://www.osti.gov/servlets/purl/1432854.
@article{osti_1432854,
title = {Molecular basis of human CD22 function and therapeutic targeting},
author = {Ereño-Orbea, June and Sicard, Taylor and Cui, Hong and Mazhab-Jafari, Mohammad T. and Benlekbir, Samir and Guarné, Alba and Rubinstein, John L. and Julien, Jean-Philippe},
abstractNote = {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.},
doi = {10.1038/s41467-017-00836-6},
journal = {Nature Communications},
number = [1],
volume = [8],
place = {United States},
year = {2017},
month = {10}
}

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Cited by: 27 works
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