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Molecular basis of human CD22 function and therapeutic targeting
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DOI：10.1038/s41467-017-00836-6.png)
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Abstract
En 中文
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 angstrom resolution, which reveals that specificity for alpha 2-6 sialic acid ligands is dictated by a pre-formed beta-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 angstrom 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.
Keywords:
RESOLUTION STRUCTURE
MONOCLONAL-ANTIBODY
EPITOPE SPECIFICITY
CRYSTAL-STRUCTURE
STRUCTURAL BASIS
CELL-FUNCTION
SIALIC ACIDS
B-CELLS
LIGANDS
SYSTEM
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