Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22

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198

Here we characterize the properties and expression pattern of Siglec-9 (sialic acid-binding Ig-like lectin-9), a new member of the Siglec subgroup of the immunoglobulin superfamily. A full-length cDNA encoding Siglec-9 was isolated from a dibutyryl cAMP-treated HL-60 cell cDNA library. Siglec-9 is predicted to contain three extracellular immunoglobulin-like domains that comprise an N-terminal V-set domain and two C2-set domains, a transmembrane region and a cytoplasmic tail containing two putative tyrosine-based signaling motifs. Overall, Siglec-9 is ϳ80% identical in amino acid sequence to Siglec-7, suggesting that the genes encoding these two proteins arose relatively recently by gene duplication. Binding assays showed that, similar to Siglec-7, Siglec-9 recognized sialic acid in either the ␣2,3-or ␣2,6-glycosidic linkage to galactose. Using a specific mAb, Siglec-9 was found to be expressed at high or intermediate levels by monocytes, neutrophils, and a minor population of CD16 Sialic acid-binding immunoglobulin-like lectins (Siglecs) 1 are transmembrane sialic acid-binding proteins of the immunoglobulin (Ig) superfamily characterized by the presence of an N-terminal V-set Ig-like domain and variable numbers of C2 set domains (1). The first Siglecs to be characterized were sialoadhesin/Siglec-1, CD22/Siglec-2, CD33/Siglec-3 and myelin-associated glycoprotein/Siglec-4 which share ϳ25-30% sequence identity within the extracellular regions (2). Recent studies (3-8) have uncovered the existence of a cluster of genes on human chromosome 19q13.3-4 that encode novel Siglecs highly related to CD33. This CD33-related subgroup includes Siglecs-3, -5, -6, -7, and -8, each of which share ϳ50 -70% sequence identity, suggesting that the genes encoding them have arisen relatively recently by gene duplication and exon shuffling. Despite their sequence similarity, all novel Siglecs characterized to date are expressed on distinct subsets of hemopoietic cells, such as neutrophils (Siglec-5) (4), B cells (Siglec-6) (8), natural killer (NK) cells (Siglec-7) (5, 6), and eosinophils (Siglec-8) (7). Each of these Siglecs also exhibits distinct carbohydrate binding properties (4, 5, 7-10). These differences in expression and ligand binding suggest that each Siglec mediates a specific, nonredundant function in hemopoietic cell biology.The cytoplasmic tails of most CD33-related Siglecs contain two homologous tyrosine-based motifs, one of which fits the consensus for immune receptor tyrosine-based inhibitory motifs (ITIMs) (11). The presence of one or more ITIMs has been described in a growing number of other leukocyte membrane receptors, many of which are tightly linked to CD33-related Siglecs on chromosome 19q13.4, in a region known as the leukocyte receptor cluster (12). The consensus that has emerged is that receptors bearing ITIMs mediate inhibitory functions when co-cross-linked with activating receptors bearing tyrosine based activatory motifs (reviewed in Ref. 11). This has been shown to be due to tyrosine phosphorylation of t...

Section: Resultssupporting

confidence: 91%

Siglec-9, a Novel Sialic Acid Binding Member of the Immunoglobulin Superfamily Expressed Broadly on Human Blood Leukocytes

Zhang

Nicoll²,

Jones

et al. 2000

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“…Previous reports have also demonstrated that siglecs exhibit differential specificity for sialic acids commonly found in mammalian species including NeuAc, NeuGc, and 9-O-acetyl-NeuAc (3,4,29,32). Indeed, although human CD22 binds equally well to ␣2-6 sialosides containing either NeuAc or NeuGc, murine CD22 exhibits a strong preference for NeuGc (32,39,63).…”

Section: Potent Inhibition Of Mag (Siglec-4) By O-linked Sialosides-tomentioning

confidence: 96%

Sialoside Specificity of the Siglec Family Assessed Using Novel Multivalent Probes

Blixt¹,

Collins²,

Nieuwenhof³

et al. 2003

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111

Ten of the 11 known human siglecs or their murine orthologs have been evaluated for their specificity for over 25 synthetic sialosides representing most of the major sequences terminating carbohydrate groups of glycoproteins and glycolipids. Analysis has been performed using a novel multivalent platform comprising biotinylated sialosides bound to a streptavidin-alkaline phosphatase conjugate. Each siglec was found to have a unique specificity for binding 16 different sialoside-streptavidin-alkaline phosphatase probes. The relative affinities of monovalent sialosides were assessed for each siglec in competitive inhibition studies. The quantitative data obtained allows a detailed analysis of each siglec for the relative importance of sialic acid and the penultimate oligosaccharide sequence on binding affinity and specificity. Most remarkable was the finding that myelin-associated glycoprotein (Siglec-4) binds with 500 -10,000-fold higher affinity to a series of mono-and di-sialylated derivatives of the O-linked T-antigen (Gal␤(1-3)-GalNAc␣OThr) as compared with ␣-methyl-NeuAc.

“…For sialoadhesin, modification of the C-8 or C-9 hydroxyl, the acetamido nitrogen or methyl group (33), or the C-1 carboxylic acid eliminated binding (Figs. 5 and 6), whereas removal of the C-4 or C-7 hydroxyl was without effect.…”

Section: Figmentioning

confidence: 99%

Binding Specificities of the Sialoadhesin Family of I-type Lectins

Collins¹,

Kiso²,

Hasegawa³

et al. 1997

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144

The carbohydrate binding specificities of three sialoadhesins, a subgroup of I-type lectins (immunoglobulin superfamily lectins), were compared by measuring lectin-transfected COS cell adhesion to natural and synthetic gangliosides. The neural sialoadhesins, myelinassociated glycoprotein (MAG) and Schwann cell myelin protein (SMP), had similar and stringent binding specificities. Each required an ␣2,3-linked sialic acid on the terminal galactose of a neutral saccharide core, and they shared the following rank-order potency of binding: G Q1b␣ > > G D1a ‫؍‬ G T1b > > G M3 ‫؍‬ G M4 > > G M1 , G D1b , G D3 , G Q1b (nonbinders). In contrast, sialoadhesin had less exacting specificity, binding to gangliosides that bear either terminal ␣2,3-or ␣2,8-linked sialic acids with the following rank-order potency of binding: Sialoadhesins (1) are a structurally and functionally related family consisting of five immunoglobulin superfamily lectins (I-type lectins) (2) including myelin-associated glycoprotein (MAG), 1 Schwann cell myelin protein (SMP), CD22, CD33, and sialoadhesin. MAG and SMP are found on oligodendroglia and Schwann cells in the nervous system (3, 4), CD22 is expressed on a subset of B lymphocytes, sialoadhesin on a subset of macrophages, and CD33 on cells of myelomonocytic lineage. Sialoadhesins have been proposed to mediate cell-cell recognition, perhaps via their carbohydrate binding activities (5-7). Each sialoadhesin family member has two or more Ig-like domains: an amino-terminal V-set domain followed by one or more (up to 16) C2-set domains (8). Domain deletion and sitedirected mutagenesis of sialoadhesin and CD22 localize their carbohydrate-binding sites to the amino-terminal V-set domain, with contributions (for CD22) from the adjoining C2-set domain. These first two domains share very high amino acid sequence similarity between MAG and SMP (Ͼ70%) and significant similarity across all I-type lectins (Ͼ30% in pairwise comparisons) (2,8,9).Each I-type lectin binds to carbohydrate structures bearing a nonreducing terminal sialic acid (1,6,10). Sialic acids are a common nonreducing terminus of vertebrate glycoconjugates and appear to play uniquely important roles in recognition phenomena. Because sialic acids may be linked to Gal, GalNAc, or other sialic acid residues at various positions and because they may carry different substituents on their 9-carbon base structure, the sialic acids represent a diverse family of carbohydrate determinants (11). In certain sialic acid-dependent recognition systems, determinant stringency is low. For example, selectins bind to oligosaccharides bearing truncated sialic acids (12) or appropriately placed anionic groups (sulfates, carboxylic acids) otherwise unrelated to the sialic acid structure (13-16). In contrast, sialoadhesins appear to have more stringent sialic acid specificities (see "Discussion") (9). In this study, we used cells expressing different sialoadhesins to explore and compare the fine structural preferences of their binding to target sialylated glycoconju...