scholarly journals The three members of the selectin receptor family recognize a common carbohydrate epitope, the sialyl Lewis(x) oligosaccharide

1992 ◽  
Vol 117 (4) ◽  
pp. 895-902 ◽  
Author(s):  
C Foxall ◽  
SR Watson ◽  
D Dowbenko ◽  
C Fennie ◽  
LA Lasky ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Leukocyte Adhesion ◽  
Structural Features ◽  
Sialyl Lewis X ◽  
Lewis X ◽  
Leukocyte Adhesion Molecule ◽  
Lectin Domain ◽  
Calcium Dependent ◽  
Carbohydrate Epitope ◽  
Sialyl Lewis

The selectins (lectin-EGF-complement binding-cell adhesion molecules [LEC-CAMs]) are a family of mammalian receptors implicated in the initial interactions between leukocytes and vascular endothelia, leading to lymphocyte homing, platelet binding, and neutrophil extravasation. The three known selectins, L-selectin (leukocyte adhesion molecule-1 [LECAM-1]), E-selectin (endothelial-leukocyte adhesion molecule-1 [ELAM-1]), and P-selectin (GMP-140) share structural features that include a calcium-dependent lectin domain. The sialyl Lewis(x) carbohydrate epitope has been reported as a ligand for both E- and P-selectins. Although L-selectin has been demonstrated to bind to carbohydrates, structural features of potential mammalian carbohydrate ligand(s) have not been well defined. Using an ELISA developed with a sialyl Lewis(x)-containing glycolipid and an E-selectin-IgG chimera, we have demonstrated the direct binding of the L-selectin-IgG chimera to sialyl Lewis(x). This recognition was calcium dependent, and could be blocked by Mel-14 antibody but not by other antibodies. Recognition was confirmed by the ability of cells expressing the native L-selectin to adhere to immobilized sialyl Lewis(x). These data suggest that the sialyl Lewis(x) oligosaccharide may form the basis of a recognition domain common to all three selectins.

scholarly journals The selectin GMP-140 binds to sialylated, fucosylated lactosaminoglycans on both myeloid and nonmyeloid cells.

1991 ◽  
Vol 115 (2) ◽  
pp. 557-564 ◽  
Author(s):  
Q Zhou ◽  
K L Moore ◽  
D F Smith ◽  
A Varki ◽  
R P McEver ◽  
...  
Keyword(s):  
Leukocyte Adhesion ◽  
Structural Features ◽  
Sialyl Lewis X ◽  
Lewis X ◽  
Ligand Interaction ◽  
Sialyl Lewis ◽  
Activated Platelets ◽  
Granule Membrane ◽  
Myeloid Leukocytes ◽  
Endothelial Leukocyte Adhesion Molecule

Granule membrane protein-140 (GMP-140) is an inducible receptor for myeloid leukocytes on activated platelets and endothelium. Like other selectins, GMP-140 recognizes specific oligosaccharide ligands. However, prior data on the nature of these ligands are contradictory. We investigated the structural features required for ligand interaction with GMP-140 using purified GMP-140, cells naturally expressing specific oligosaccharides, and cells expressing cloned glycosyltransferases. Like the related selectin endothelial leukocyte adhesion molecule-1 (ELAM-1), GMP-140 recognizes alpha(2-3)sialylated, alpha(1-3)fucosylated lactosaminoglycans on both myeloid and nonmyeloid cells, including the sequence Neu5Ac alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNac beta-R (sialyl Lewis x). Recognition requires sialic acid, because cells expressing large amounts of Lewis x, but not sialyl Lewis x, do not interact with GMP-140. Although sialyl Lewis x is expressed by both myeloid HL-60 cells and CHO cells transfected with an alpha 1-3/4 fucosyltransferase, GMP-140 binds with significantly higher affinity to HL-60 cells. Thus, the sialyl Lewis x tetrasaccharide may require additional structural modifications or specific presentations in order for leukocytes in flowing blood to interact rapidly and with high affinity to GMP-140 on activated platelets or endothelium.

Glycan engineering using synthetic ManNAc analogues enhances sialyl-Lewis-X expression and adhesion of leukocytes

2021 ◽  
Author(s):  
Anam Tasneem ◽  
Shubham Parashar ◽  
Tanya Jain ◽  
Simran Aittan ◽  
Jyoti Rautela ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Inflammatory Diseases ◽  
Leukocyte Adhesion ◽  
Fold Increase ◽  
Sialyl Lewis X ◽  
Lewis X ◽  
Sialyl Lewis ◽  
Acute Myeloid Leukemia Cells ◽  
Coated Surfaces ◽  
Cell Cell

Cell surface glycans, depending on their structures and dynamic modifications, act as the first point of contact and regulate cell-cell, cell-matrix, and cell-pathogen interactions. Particularly, the sialyl-Lewis-X (sLeX, CD15s) tetrasaccharide epitope, expressed on both glycoproteins and gangliosides, participates in leukocyte extravasation via interactions with selectins expressed on endothelial cells, lymphocytes, and platelets (CD62-E/L/P). Neutrophils carrying sLeX epitopes are thought to be responsible for chronic inflammatory diseases resulting in plaque formation and atherosclerosis. Intense efforts have been devoted to the development of sLeX mimetics for inhibition of cell adhesion. On the other hand, dysregulated expression of sLeX and poor extravasation are the major underlying causes of leukocyte adhesion deficiency-II (LAD-II) disorders that result in frequent infections and poor immune response. We hypothesized that metabolic processing of peracetyl N-(cycloalkyl)acyl-D-mannosamine derivatives, through the sialic acid pathway, might result in the expression of sialoglycans with altered hydrophobicity which in-turn could modulate their binding to endogenous lectins, including selectins. Herein, we show that treatment of HL-60 (human acute myeloid leukemia) cells with peracetyl N-cyclobutanoyl-D-mannosamine (Ac4ManNCb), at 50 microM for 48 h, resulted in a robust three to four fold increase in the binding of anti-sLeX (CSLEX1) antibody and enhanced cell adhesion to E-selectin coated surfaces; while the corresponding straight-chain analogue, peracetyl N-pentanoyl-D-mannosamine (Ac4ManNPent), and peracetyl N-cyclopropanoyl-D-mannosamine (Ac4ManNCp) both resulted in 2.0-2.5fold increase compared to controls. The ability to enhance sLeX expression using small molecules has the potential to provide novel opportunities to address challenges in the treatment of immune deficiency disorders.

scholarly journals P- and E-selectin use common sites for carbohydrate ligand recognition and cell adhesion.

1993 ◽  
Vol 120 (5) ◽  
pp. 1227-1235 ◽  
Author(s):  
D V Erbe ◽  
S R Watson ◽  
L G Presta ◽  
B A Wolitzky ◽  
C Foxall ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Sialic Acid ◽  
Sialyl Lewis X ◽  
Homologous Region ◽  
Carbohydrate Recognition ◽  
Lectin Domain ◽  
Calcium Dependent ◽  
Sialyl Lewis ◽  
Adhesive Interactions ◽  
Carbohydrate Ligand

The selectins are a family of three calcium-dependent lectins that mediate adhesive interactions between leukocytes and the endothelium during normal and abnormal inflammatory episodes. Previous work has implicated the carbohydrate sialyl Lewis(x) (sLe(x); sialic acid alpha 2-3 galactose beta 1-4 [Fucose alpha 1-3] N-acetyl glucosamine) as a component of the ligand recognized by E- and P-selectin. In the case of P-selectin, other components of the cell surface, including 2'6-linked sialic acid and sulfatide (galactose-4-sulfate ceramide), have also been proposed for adhesion mediated by this selectin. We have recently defined a region of the E-selectin lectin domain that appears to be directly involved with carbohydrate recognition and cell adhesion (Erbe, D. V., B. A. Wolitzky, L. G. Presta, C. R. Norton, R. J. Ramos, D. K. Burns, R. M. Rumberger, B. N. N. Rao, C. Foxall, B. K. Brandley, and L. A. Lasky. 1992. J. Cell Biol. 119:215-227). Here we describe a similar analysis of the P-selectin lectin domain which demonstrates that a homologous region of this glycoprotein's lectin motif is involved with carbohydrate recognition and cell binding. In addition, we present evidence that is inconsistent with a biological role for either 2'6-linked sialic acid or sulfatide in P-selectin-mediated adhesion. These results suggest that a common region of the E- and P-selectin lectin domains appears to mediate carbohydrate recognition and cell adhesion.

scholarly journals Fluorinated per-acetylated GalNAc metabolically alters glycan structures on leukocyte PSGL-1 and reduces cell binding to selectins

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1303-1312 ◽  
Author(s):  
Dhananjay D. Marathe ◽  
Alexander Buffone ◽  
E. V. Chandrasekaran ◽  
Jun Xue ◽  
Robert D. Locke ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Leukocyte Adhesion ◽  
Human Leukocyte ◽  
Sialyl Lewis X ◽  
Metabolic Inhibitor ◽  
Growth Media ◽  
Cell Binding ◽  
Lewis X ◽  
Sialyl Lewis

Abstract Novel strategies to control the binding of adhesion molecules belonging to the selectin family are required for the treatment of inflammatory diseases. We tested the possibility that synthetic monosaccharide analogs can compete with naturally occurring sugars to alter the O-glycan content on human leukocyte cell surface selectin-ligand, P-selectin glycoprotein ligand-1 (PSGL-1). Resulting reduction in the sialyl Lewis-X–bearing epitopes on this ligand may reduce cell adhesion. Consistent with this hypothesis, 50μM per-acetylated 4F-GalNAc added to the growth media of promyelocytic HL-60 cells reduced the expression of the cutaneous lymphocyte associated-antigen (HECA-452 epitope) by 82% within 2 cell doubling cycles. Cell binding to all 3 selectins (L-, E-, and P-selectin) was reduced in vitro. 4F-GalNAc was metabolically incorporated into PSGL-1, and this was accompanied by an approximately 20% reduction in PSGL-1 glycan content. A 70% to 85% reduction in HECA-452 binding epitope and N-acetyl lactosamine content in PSGL-1 was also noted on 4F-GalNAc addition. Intravenous 4F-GalNAc infusion reduced leukocyte migration to the peritoneum in a murine model of thioglycolate-induced peritonitis. Thus, the compound has pharmacologic activity. Overall, the data suggest that 4F-GalNAc may be applied as a metabolic inhibitor to reduce O-linked glycosylation, sialyl Lewis-X formation, and leukocyte adhesion via the selectins.

scholarly journals Identification of Podocalyxin-like Protein as a High Endothelial Venule Ligand for L-selectin: Parallels to CD34

1998 ◽  
Vol 187 (12) ◽  
pp. 1965-1975 ◽  
Author(s):  
Christopher Sassetti ◽  
Kirsten Tangemann ◽  
Mark S. Singer ◽  
David B. Kershaw ◽  
Steven D. Rosen
Keyword(s):  
Adhesion Molecule ◽  
Leukocyte Adhesion ◽  
Structural Features ◽  
High Endothelial Venules ◽  
Lectin Domain ◽  
Kidney Glomerulus ◽  
Selectin Ligand ◽  
Definition Of ◽  
Secondary Lymphoid Organs

The leukocyte adhesion molecule, L-selectin, mediates the recruitment of lymphocytes to secondary lymphoid organs via interactions with specific ligands presented on high endothelial venules (HEV). Although the HEV-derived ligands for L-selectin are still incompletely defined, they share a common sialomucin-like structure which is thought to present clustered oligosaccharides to the lectin domain of L-selectin. Podocalyxin-like protein (PCLP) is a transmembrane sialomucin that is similar in structure to the well-characterized L-selectin ligand CD34. PCLP has been shown previously to be expressed on the foot processes of podocytes in the kidney glomerulus as well as on vascular endothelium at some sites. We have determined that PCLP is present on HEV, where it binds to both recombinant L-selectin and the HEV-specific monoclonal antibody MECA-79. Furthermore, purified HEV-derived PCLP is able to support the tethering and rolling of lymphocytes under physiological flow conditions in vitro. These results suggest a novel function for PCLP as an adhesion molecule and allow the definition of conserved structural features in PCLP and CD34, which may be important for L-selectin ligand function.

scholarly journals Replacing a Lectin Domain Residue in L-selectin Enhances Binding to P-selectin Glycoprotein Ligand-1 but Not to 6-Sulfo-sialyl Lewis x

2008 ◽  
Vol 283 (17) ◽  
pp. 11493-11500 ◽  
Author(s):  
Arkadiusz G. Klopocki ◽  
Tadayuki Yago ◽  
Padmaja Mehta ◽  
Jun Yang ◽  
Tao Wu ◽  
...  
Keyword(s):  
Sialyl Lewis X ◽  
Lewis X ◽  
Lectin Domain ◽  
Sialyl Lewis
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