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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 ?2-6 sialic acid ligands is dictated by a pre-formed ?-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.

SUBMITTER: Ereno-Orbea J

PROVIDER: S-EPMC5624926 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Molecular basis of human CD22 function and therapeutic targeting.

Ereño-Orbea June J Sicard Taylor T Cui Hong H Mazhab-Jafari Mohammad T MT Benlekbir Samir S Guarné Alba A Rubinstein John L JL Julien Jean-Philippe JP

Nature communications 20171002 1

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 ecto ...[more]

PMID: 28970495

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Molecular basis of human CD22 function and therapeutic targeting.

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Molecular basis of human CD22 function and therapeutic targeting.

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