Insights into the Molecular Basis of Leukocyte Tethering and Rolling Revealed by Structures of P- and E-Selectin Bound to SLeX and PSGL-1

  title={Insights into the Molecular Basis of Leukocyte Tethering and Rolling Revealed by Structures of P- and E-Selectin Bound to SLeX and PSGL-1},
  author={William Stuart Somers and Jin Tang and Gray D. Shaw and Raymond T. Camphausen},

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Molecular Basis of Leukocyte Rolling on PSGL-1

The effect of post-translational modifications of PSGL-1 including Tyr sulfation and presentation of sialylated and fucosylated O-glycans for L-selectin binding is examined to pinpoint the structural characteristics of PS GL-1 that are required for optimal interactions with L- selectin and may be responsible for the specific kinetic and mechanical bond properties of the L- Selectin-PSGL- 1 adhesion receptor-counterreceptor pair.

Tyrosine sulfation enhances but is not required for PSGL-1 rolling adhesion on P-selectin.

Affinity and kinetics of sialyl Lewis-X and core-2 based oligosaccharides binding to L- and P-selectin.

Soluble oligosaccharide mimetics of natural selectin ligands act as competitive inhibitors of leukocyte adhesion in models of inflammation. We quantified the binding of simple oligosaccharides based

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The N-terminal peptide of PSGL-1 can mediate adhesion to trauma-activated endothelium via P-selectin in vivo.

Results indicate that the N-terminal peptide of PSGL-1 can mediate adhesion to trauma-activated microvascular endothelium via P-selectin in vivo.

Model Glycosulfopeptides from P-selectin Glycoprotein Ligand-1 Require Tyrosine Sulfation and a Core 2-branched O-Glycan to Bind to L-selectin*

It is demonstrated that L-selectin binds with high affinity to the N-terminal region of PSGL-1 through cooperative interactions with three sulfated tyrosine residues and an appropriately positioned C2-O-sLex O-glycan.

P-selectin Glycoprotein Ligand-1 Decameric Repeats Regulate Selectin-dependent Rolling under Flow Conditions*

Results indicate that the role of decamers is to extend PSGL-1 N terminus far above the cell surface to support and stabilize leukocyte rolling on L- or P-selectin-dependent rolling.

Human P-selectin Glycoprotein Ligand-1 (PSGL-1) Interacts with the Skin-associated Chemokine CCL27 via Sulfated Tyrosines at the PSGL-1 Amino Terminus*

A role for PSGL-1 in regulating chemokine-mediated responses, in addition to its role as a selectin ligand, is suggested.



Tyrosine replacement in P-selectin glycoprotein ligand-1 affects distinct kinetic and mechanical properties of bonds with P- and L-selectin.

It is revealed that L-selectin dissociated faster from single-Tyr than wild-type PSGL-1 at higher shear but not at lower shear, and tyrosine replacements in PS GL-1 affect distinct kinetic and mechanical properties of bonds with P- and L- selectin.

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

Structural features of potential mammalian carbohydrate ligand(s) have not been well defined and data suggest that the sialyl Lewis(x) oligosaccharide may form the basis of a recognition domain common to all three selectins.

Noncovalent Association of P-selectin Glycoprotein Ligand-1 and Minimal Determinants for Binding to P-selectin*

It is demonstrated that Cys320-dependent dimerization of PS GL-1 is not required for binding to P-selectin and that a small monomeric fragment of PSGL- 1 is sufficient for P- selectin recognition.

The P-selectin glycoprotein ligand from human neutrophils displays sialylated, fucosylated, O-linked poly-N-acetyllactosamine.

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Visualization of P-selectin Glycoprotein Ligand-1 as a Highly Extended Molecule and Mapping of Protein Epitopes for Monoclonal Antibodies (*)

The results demonstrate that PSGL-1 is a long, extended molecule and suggest that the P-selectin binding site is located near the N terminus, well above the membrane, which may facilitate interactions of PS GL-1 with P- selectin under shear stress.

Affinity and Kinetic Analysis of P-selectin Binding to P-selectin Glycoprotein Ligand-1*

It is concluded that monomeric P-selectin binds to PSGL-1 with fast association and dissociation rates and relatively high affinity, which may be important for efficient tethering and rolling of leukocytes at physiologic densities of PS GL-1 and P- selectin.

Interaction between soluble P-selectin and soluble P-selectin glycoprotein ligand 1: equilibrium binding analysis.

Results indicate high-affinity interaction between P-selectin and PSGL-1 in a system in which both protein species are soluble and lack transmembrane domains and the fucosylation pattern of PS GL-1 can affect its affinity for P- selectin.

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L-selectin, a lectin-like receptor, mediates rolling of lymphocytes on high endothelial venules (HEVs) in secondary lymphoid organs by interacting with HEV ligands, candidates for which are glycosylation- dependent cell adhesion molecule 1 (GlyCAM-1), CD34, and podocalyxin.

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