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Terminal Epitope-Dependent Branch Preference of Siglecs Toward N-Glycans.

ABSTRACT: Siglecs are sialic acid-binding immunoglobulin-like lectins that play vital roles in immune cell signaling. Siglecs help the immune system distinguish between self and nonself through the recognition of glycan ligands. While the primary binding specificities of Siglecs are known to be divergent, their specificities for complex glycans remain unclear. Herein, we determined N-glycan binding profiles of a set of Siglecs by using a complex asymmetric N-glycan microarray. Our results showed that Siglecs had unique terminal epitope-dependent branch preference when recognizing asymmetric N-glycans. Specifically, human Siglec-3, -9, and -10 prefer the α1-3 branch when Siaα2-6Galβ1-4GlcNAc terminal epitope serves as the binding ligand but prefer the opposite α1-6 branch when Siaα2-3Galβ1-4GlcNAc epitope serves as the ligand. Interestingly, Siglec-10 exhibited dramatic binding divergence toward a pair of Neu5Ac-containing asymmetric N-glycan isomers, as well as their Neu5Gc-containing counterparts. This new information on complex glycan recognition by Siglecs provides insights into their biological roles and applications.

SUBMITTER: Wang S

PROVIDER: S-EPMC8116747 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aberrant glycosylation, a common feature associated with malignancy, has been implicated in important events during cancer progression. Our understanding of the role of glycans in cancer has grown exponentially in the last few years, concurrent with important advances in glycomics and glycoproteomic technologies, paving the way for the validation of a number of glycan structures as potential glycobiomarkers. However, the molecular bases underlying cancer-associated glycan modifications are still far from understood. Glycans exhibit a natural heterogeneity, crucial for their diverse functional roles as specific carriers of biologically relevant information. This information is decoded by families of proteins named lectins, including sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), C-type lectin receptors (CLRs), and galectins. Siglecs are primarily expressed on the surface of immune cells and differentially control innate and adaptive immune responses. Among CLRs, selectins are a family of cell adhesion molecules that mediate interactions between cancer cells and platelets, leukocytes, and endothelial cells, thus facilitating tumor cell invasion and metastasis. Galectins, a family of soluble proteins that bind ?-galactoside-containing glycans, have been implicated in diverse events associated with cancer biology such as apoptosis, homotypic cell aggregation, angiogenesis, cell migration, and tumor-immune escape. Consequently, individual members of these lectin families have become promising targets for the design of novel anticancer therapies. During the past decade, a number of inhibitors of lectin-glycan interactions have been developed including small-molecule inhibitors, multivalent saccharide ligands, and more recently peptides and peptidomimetics have offered alternatives for tackling tumor progression. In this article, we review the current status of the discovery and development of chemical lectin inhibitors and discuss novel strategies to limit cancer progression by targeting lectin-glycan interactions.

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Terminal Epitope-Dependent Branch Preference of Siglecs Toward N-Glycans.

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